WO2018148598A1 - Compositions pour le traitement du cancer du sein - Google Patents

Compositions pour le traitement du cancer du sein Download PDF

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WO2018148598A1
WO2018148598A1 PCT/US2018/017702 US2018017702W WO2018148598A1 WO 2018148598 A1 WO2018148598 A1 WO 2018148598A1 US 2018017702 W US2018017702 W US 2018017702W WO 2018148598 A1 WO2018148598 A1 WO 2018148598A1
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substituted
unsubstituted
independently
membered
heteroaryl
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PCT/US2018/017702
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Daniel K. Nomura
Lindsay S. ROBERTS
Carl C. WARD
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The Regents Of The University Of California
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/385—Saturated compounds containing a keto group being part of a ring

Definitions

  • TNBCs triple-negative breast cancers
  • R 1 is independently halogen, -CXS, -CHX ⁇ , -CH2X 1 , -OCX ⁇ , - OCH2X 1 , -OCHX 1 !, -CN, -SOniR 1D , -SOvi R 1A R 1B , - HC(0) R 1A R 1B , -N(0) m i, - R 1A R 1B , -C(0)R 1C , -C(0)-OR l c , -C(0) R 1A R 1B , -OR 1D , - R 1A S0 2 R 1D , - R 1A C(0)R 1C , - R 1A C(0)0 R 1 C , - R 1A 0R 1C , -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or un
  • R 1 is independently halogen, -CX 2 3 , -CHX 2 2 , -CH 2 X 2 , -OCX 2 3 , -
  • R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , and R 2D is independently
  • R 1A and R 1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R 2A and R 2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.
  • Each X, X 1 , and X 2 is independently -F, -CI, -Br, or -I.
  • the symbols nl and n2 are independently an integer from 0 to 4.
  • a PTGR1 inhibitor In an aspect is provided a PTGR1 inhibitor. In embodiments, the PTGR1 inhibitor is a compound described herein. [0008] In an aspect is provided a method of treating cancer, the method including administering to a subject in need thereof an effective amount of a PTGRl inhibitor. In embodiments, the PTGRl inhibitor is a compound described herein.
  • a method of treating triple negative breast cancer including administering to a subject in need thereof an effective amount of a PTGRl inhibitor.
  • the PTGRl inhibitor is a compound described herein.
  • a method of treating cancer including administering to a subject in need thereof an effective amount of a compound described herein.
  • a method of treating a disease associated with PTGRl activity including administering to a subject in need thereof an effective amount of a PTGRl inhibitor.
  • a method of inhibiting PTGRl activity including contacting the PTGRl with a PTGRl inhibitor.
  • a method of inhibiting PTGRl activity including contacting the PTGRl with a compound described herein.
  • a PTGRl protein covalently bonded to a PTGRl inhibitor (a PTGRl protein-PTGRl inhibitor complex).
  • a PTGRl protein covalently bonded to a compound described herein.
  • FIGS. 1 A-1C Screening a library of drugs and drug candidates in TNBC cells.
  • FIGS. ⁇ , ⁇ A library of drugs and drug candidates were screened in 231MFP and HCC38 TNBC cell lines for impairments in serum -free cell survival.
  • FIG. 1C Cell survival of drugs and drug candidates that reproducibly and significantly impaired 231MFP, HCC38, and HCC70 viability by >50 %.
  • FIG. 1C A x-axis (left to right):
  • Mitoxantrone HCI ES 1-09, TIC 10, Romidepsin (FK228, Depsipeptide), Crizotinib (PF- 02341066), Mitoxantrone, AT9283, MI-773 (SAR405838), SH -4-54, NU7441 (KU-57788), INH6, INH1, MLN2238, MLN9708, Daunorubicin HCI (Daunomycin HCI), YM155, WP1130, TG101348 (SAR302503), Idarubicin HCI, JNK-IN-8, GW4064, Doxorubicin (Adriamycin), GSK461364, PTC-209 HBr, RG-7112, SRT1720, Dacomitinib (PF299804,PF- 00299804), Torin 2, Licochalcone A, Imatinib (Gleevec), BI6727 (Volasertib), PF-
  • Picropodophyllin PPP
  • PD 0332991 Palbociclib
  • HCI SU11274, AZ 3146, HJC0350
  • Sotrastaurin (AEB071), BX-795, WAY-362450, PF-562271, LY294002, INJ-38877605, Dalcetrapib (JTT-705), Triptolide, PND-1186 (VS-4718), XMD8-92, Cyclosporin A
  • Temsirolimus (Torisel), Aminoglutethimide (Cytadren), CYC116, TPCA-1, YH239-EE, 4SC-202, Maraviroc, KU-55933, AG14361, CH5138303, AZD1208, Lapatinib Ditosylate (Tykerb), BIRB 796 (Doramapimod), E7080 (Lenvatinib), Tubacin, Phosphoramidon Disodium Salt, ABT-888 (Veliparib), Mycophenolate mofetil (CellCopt), RG108, Pioglitazone (Actos), Lenalidomide (Revlimid), R04929097, Gossypol, VER-50589, AMG 900, PF 573228, Lonidamine, PF-04217903, Z-VAD-FMK, BMS-599626 (AC480),
  • Toremifene Citrate (Fareston, Acapodene), Mifepnstone (Mifeprex), Gefitinib (Iressa), Pornalidomide, Afuresertib (GSK2110183), WIKI4, Tipifarnib (Zarnestra), SGX-523, TW- 37, BV-6, CHIR-99021 (CT99021) HCI, SB 203580, CEP33779, Vismodegib (GDC-0449), MK-0752, Oltipraz, 2-Methoxyestradiol, Ifosfamide, Bexarotene, Medroxyprogesterone acetate, Santacruzamate A (CAY10683), AUY922 (NVP-AUY922), Hydroxyurea
  • Fulvestrant (Faslodex), YO-01027, Enzastaurin (LY317615), Mesna (Uromitexan, Mesnex), JNfC Inhibitor IX, Obatoclax mesylate (GXl 5-070), Azacitidine (Vidaza), PU-H71, Bosutinib (SKI-606), DMXAA (ASA404), ABC294640, GF109203X, PHA-665752, Flutamicle
  • LY2874455 PX-478 2HCI, Exemestane, Crenolanib (CP-868596), Dovitinib (TKI-258), Febuxostat (Uloric), SB 431542, Lomustine (CeeNU), PH-797804, Altretamine (Hexalen), Paclitaxel (Taxol), Epothilone B (EP0906), Zibotentan (ZD4054), Cediranib (AZD2171), EX 527, Vemurafenib (PLX4032), Floxuridine (Fludara), Andarine (GTX-007), Cladribine, Thalidomide, BMS 794833, Itraconazole (Sporanox), AZD8186, Rapamycin (Sirolimus), Tretinoin (Aberela), Chrysophanic acid (Chrysophanol), GW3965 HCI, BI18021, Celecoxib, GDC
  • Rosiglitazone (Avandia), Roscovitine (Seliciclib, CYC202), BAY 11-7082 (BAY 11-7821), Mycophenolic (Mycophenolate), JNJ 26854165 (Serdemetan), Ro3280, K- Ras(G12C) inhibitor 9, 3-Methyladenine, INK 128 (MLN0128), Nutlin-3a, dacarbazine (DTIC-Dome), Geldanamycin, P0173955, VS-5584 (SB2343), Decitabine, DCC-2036 (Rebastinib), SF1670, Vorinostat (SAHA), Busulfan (Myleran, Busulfex), TAME, Telatinib (BAY 57-9352), Olaparib (AZD2281), Teniposide (Vumon), ABT-737, Fludarabine
  • FIG. IB x-axis (left to right): AEE788 (NVP-AEE788),
  • Vemurafenib (PLX4032), Gossypol, Mitoxantrone HCI, PHA-793887, SH-4-54, ESI-09,
  • WP1130 Doxorubicin (Adriamycin), PIK-93, G-749, B16727 (Volasfirtib), Pelitinib (EKB- 569), Licochalcone A, Daunorubicin HCI (Daunomycin HCI), CX-6258 HCI, Mitroxantrone, Romidepsin (FK228, Depsipeptide), PF-3758209, RG-7112, Torin 2, Xanthohumol,
  • Picropodophyliin PPP
  • CYT997 Lexibulin
  • Gemcitabine Gemzar
  • PTC-209 HBr Regorafenib
  • Regorafenib BAY 73-4506
  • SB939 Pracinostat
  • Topotecan HCI PD 173074, PCI-24781, XL765 (SAR245409)
  • Tipifarnib Zarnestra
  • Tie2 kinase inhibitor E7080 (Lenvatinib)
  • MK- 1775 Roscovitine
  • Seliciclib CYC202
  • A17519 HCI Cabozantinib malate (XL184), 4SC- 202, INJ-7706621, PF 573228, FH535, CYC116, KU-60019, Azacitidine (Vidaza)
  • Fludarabine Fludarabine (Fludara), Dovitinib (TKI258) Lactate, Obatoclax mesylate (GX15-070), AZD8055, Etoposide (VP-16), AT9283, Nocodazole, AZD1480, BMS-536924, Vorinostat (SAHA), Docetaxel (Taxotere), Ku-0063794, Mocetinostat (MGCD0103), Cediranib
  • Rosightazone (Avandia), Epothilone B (EP0906), Quizartinib (AC220), Entinostat (MS-275, S DX-275), HO-3867, LDC000067, Sunitinib Malate (Sutent), Rigosertib (ON-01910), SF 1670, Ro3280, Bafetinib (INNO-406), CH5138303, Fludarabine Phosphate (Fludara), SB 525334, MI-773 (SAR405838), PAC-1, LY3009120, LY2603618 (IC-83), GSK2606414, AUY922 (NVP-AUY922), AZD6738, LY2228820, Simvastatin (Zocor), Adrucil
  • Vandetanib Vandetanib (Zactima), Afuresertib (GSK2110183), Temozolomide, Mercaptopunne, Imatinib (Gleevec), VS-5584 (SB2343), Dasatinib (BMS-354825), CH5183284 (Debio-1347), PCI- 32765 (lbrutinib), Aprepitant (MK-0869), Bleomycin sulfate, Endoxifen HCI, SB590885, TAK-733, ZSTK474, GSK1120212 (Trametinib), PI-103, CH5132799, Irinotecan HCI Trihydrate (Campto), Refametinib (RDEA119, Bay 86-9766), PD173955, R406 (free base), CEP33779, PH A-665752, Pexmetinib (ARRY-614), AXitinib, PD0325901, G
  • Betapar Meprednisone
  • Busulfan Myleran, Busulfex
  • Ruxolitinib (INCBO 18424), Florafur, Altretamine (Hexalen), Streptozotocin (Zanosar), and Ifosfamide.
  • FIGS. 2A-2G IsoTOP-ABPP analysis of Licochalcone A in T BC cells.
  • FIG. 2A Structure of Licochalcone A.
  • FIG. 2B Competitive isoTOP-ABPP to map Licochalcone targets.
  • Licochalcone A bears a Michael acceptor that is potentially cysteine-reactive.
  • We mapped the cysteine-reactivity of Licochalcone A by pre-incubating Licochalcone A (10 ⁇ ) for 30 min in 23 lMFP breast cancer cell proteomes, prior to labeling with the cysteine- reactive iodoacetamide-alkyne (IAyne) probe (100 ⁇ , 30 min).
  • IAyne cysteine- reactive iodoacetamide-alkyne
  • Probe labeled proteins were then tagged with an isotopically light (for control) or heavy (for Licochalcone A-treated) biotin-azide tag bearing a TEV protease recognition site by CuAAC. Control and treated proteomes were then mixed in a 1 : 1 ratio, probe labeled proteins were avi din-enriched and tryptically digested, probe-labeled tryptic peptides were avi din-enriched again, and released by TEV protease and analyzed by quantitative proteomic methods and light to heavy peptide ratios were quantified.
  • FIG. 2C Competitive isoTOP-ABPP analysis of Licochalcone A cysteine-reactivity in 23 lMFP breast cancer cell proteomes.
  • Light to heavy ratios of ⁇ 1 indicate peptides that were labeled by IAyne, but not bound by Licochalcone A.
  • the top target was C239 of PTGR1.
  • Shown in this FIG. is also validation of PTGR1 as a target of Licochalcone A.
  • Licochalcone A was pre-incubated with pure human PTGR1 protein followed by IAyne. Probe-labeled proteins conjugated to rhodamine-azide by CuAAC and analyzed by SDS/PAGE and in-gel fluorescence. (FIG.
  • FIG. 2D Crystal structure of PTGR1 showing C239 (shown in yellow) and NADP+ shown in ball and stick form. PDB structure used is 2Y05.
  • FIG. 2E PTGR1 expression in shPTGRl 231MFP cells. PTGR1 was stably knocked down with three independent shRNA oligonucleotides and expression was determined by qPCR.
  • FIGS. 3 A-3D Metabolomic profiling of drug responses in TNBC cells.
  • FIG. 3 A Metabolomic profiling of 23 lMFP TNBC cells treated with the 20 compounds that impaired TNBC cell survival. 231MFP cells were treated with DMSO vehicle or each compound (10 ⁇ ) for 6 h. Lipid levels were analyzed by single reaction monitoring (SRM)-based liquid chromatography-mass spectrometry (LC -MS/MS). Heatmap shows fold-changes in log (2) compared to vehicle-treated controls where red and blue designates increased and decreased levels, respectively.
  • FIG. 3B C16:0 AC levels in 231MFP cells treated with each of the 20 compounds that impaired TNBC cell survival. Data is from experiment described in (FIG.
  • FIG. 3C Cell survival in 231MFP cells. 231MFP cells were treated with DMSO control or deubiquitinase inhibitors PR619 and P5091 (10 ⁇ ) and serum-free cell survival was assessed 48 h after treatment by Hoescht staining.
  • FIG. 3 A y- axis (top to bottom): C16:0 FFA, C18:0 FFA, C18: l FFA, C20:4 FFA, C16:0 MAG, C18:0 MAG, C16:0/C18: l DAG, CI 6:0/C20:4 DAG, C18:0/C18: l DAG, CI 8:0/C20:4 DAG, C16:0/C16:0/C16:0 TAG, C16:0/C18: l/C16:0 TAG, C16:0/C20:4/C16:0 TAG,
  • FIGS. 4A-4D The role of AC in deubiquitinase inhibitor-mediated cell survival impairments in TNBC cells.
  • FIG. 4A 231MFP cell survival upon treatment of cells with AC. Cells were treated with AC and serum-free cell survival was assessed 48 h after treatment by Hoescht staining.
  • FIG. 4B 231MFP cell survival upon treatment of cells with AC and deubiquitinase inhibitor WP1130. Cells were co-treated with water or 06:0 AC (1 ⁇ ) at a concentration that does not impair viability when treated alone and DMSO or WP1130 and cell survival was assessed 48 h treatment by Hoescht staining.
  • FIG. 4C and 4D Oxygen consumption rates in cells treated with DMSO vehicle or AC or WP1130.
  • FIG. 6 Levels of representative lipids.
  • FIGS. 7A-7C Characterizing the role of LPE in TNBC cell survival.
  • FIG. 7 A 23 lMFP cell survival upon treatment of cells with LPE. Cells were treated with LPE and serum-free cell survival was assessed 48 h after treatment by Hoescht staining.
  • FIG. 7B 23 lMFP cell survival upon treatment of cells with LPE and protesome inhibitor MLN9708.
  • Cells were co-treated with 2: 1 chloroform:methanol or 06:0 LPE (1 ⁇ ) at a concentration that does not impair viability when treated alone and DMSO or MLN9708 and cell survival was assessed 48 h treatment by Hoescht staining.
  • FIG. 8 Model of licochalcone A binding site on PTGR1.
  • alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched carbon chain (or carbon), or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include mono-, di- and multivalent radicals.
  • the alkyl may include a designated number of carbons (e.g., C1-C10 means one to ten carbons).
  • Alkyl is an uncyclized chain.
  • saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n- butyl, t-butyl, isobutyl, sec-butyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
  • An unsaturated alkyl group is one having one or more double bonds or triple bonds.
  • Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(l,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers.
  • An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (-0-).
  • An alkyl moiety may be an alkenyl moiety.
  • An alkyl moiety may be an alkynyl moiety.
  • An alkyl moiety may be fully saturated.
  • alkenyl may include more than one double bond and/or one or more triple bonds in addition to the one or more double bonds.
  • An alkynyl may include more than one triple bond and/or one or more double bonds in addition to the one or more triple bonds.
  • alkylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited by, - CH2CH2CH2CH2-.
  • an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred herein.
  • lower alkyl or lower alkylene is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.
  • alkenylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene.
  • heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, or S), and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.
  • the heteroatom(s) e.g., O, N, P, S, B, As, or Si
  • Heteroalkyl is an uncyclized chain.
  • a heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si, or P).
  • a heteroalkyl moiety may include two optionally different heteroatoms (e.g., O, N, S, Si, or P).
  • a heteroalkyl moiety may include three optionally different heteroatoms (e.g., O, N, S, Si, or P).
  • a heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, or P).
  • a heteroalkyl moiety may include five optionally different heteroatoms (e.g., O, N, S, Si, or P).
  • a heteroalkyl moiety may include up to 8 optionally different heteroatoms (e.g., O, N, S, Si, or P).
  • heteroalkylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2- H-CH2-.
  • heteroalkylene groups heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula - C(0)2R'- represents both -C(0)2R'- and -R'C(0)2-.
  • heteroalkyl groups include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(0)R', -C(0) R', - R'R", -OR, -SR, and/or -SO2R.
  • heteroalkyl is recited, followed by recitations of specific heteroalkyl groups, such as - R'R” or the like, it will be understood that the terms heteroalkyl and - R'R" are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R" or the like.
  • cycloalkyl and heterocycloalkyl by themselves or in combination with other terms, mean, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl,” respectively. Cycloalkyl and heterocycloalkyl are not aromatic. Additionally, for
  • heterocycloalkyl a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule.
  • cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocycloalkyl examples include, but are not limited to, 1- (1,2,5, 6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3- morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl,
  • cycloalkyl en e and a “heterocycloalkylene,” alone or as part of another substituent, means a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively.
  • halo or halogen
  • haloalkyl by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
  • terms such as “haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl.
  • halo(Ci-C4)alkyl includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
  • acyl means, unless otherwise stated, -C(0)R where R is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • aryl means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently.
  • a fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring.
  • heteroaryl refers to aryl groups (or rings) that contain at least one heteroatom such as N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized.
  • heteroaryl includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring).
  • a 5,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring.
  • a 6,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring.
  • a 6,5-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring.
  • a heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom.
  • Non-limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, benzoxazoyl benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl, quinolyl, 1 -naphthyl, 2- naphthyl, 4-biphenyl, 1 -pyrrolyl, 2-pyrrolyl, 3 -pyrrolyl, 3 -pyrazolyl, 2-imidazoly
  • arylene and heteroarylene are selected from the group of acceptable substituents described below.
  • a heteroaryl group substituent may be -O- bonded to a ring heteroatom nitrogen.
  • Spirocyclic rings are two or more rings wherein adjacent rings are attached through a single atom.
  • the individual rings within spirocyclic rings may be identical or different.
  • Individual rings in spirocyclic rings may be substituted or unsubstituted and may have different substituents from other individual rings within a set of spirocyclic rings.
  • Possible substituents for individual rings within spirocyclic rings are the possible substituents for the same ring when not part of spirocyclic rings (e.g. substituents for cycloalkyl or
  • Spirocylic rings may be substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heterocycloalkylene and individual rings within a spirocyclic ring group may be any of the immediately previous list, including having all rings of one type (e.g. all rings being substituted heterocycloalkylene wherein each ring may be the same or different substituted heterocycloalkylene).
  • heterocyclic spirocyclic rings means a spirocyclic rings wherein at least one ring is a heterocyclic ring and wherein each ring may be a different ring.
  • substituted spirocyclic rings means that at least one ring is substituted and each substituent may optionally be different.
  • oxo means an oxygen that is double bonded to a carbon atom.
  • alkylarylene as an arylene moiety covalently bonded to an alkylene moiety (also referred to herein as an alkylene linker).
  • alkylarylene group has the formula:
  • An alkylarylene moiety may be substituted (e.g. with a substituent group) on the alkylene moiety or the arylene linker (e.g. at carbons 2, 3, 4, or 6) with halogen, oxo, -N 3 , - CF 3 , -CC1 3 , -CBr 3 , -CI 3 , -CN, -CHO, -OH, - H 2 , -COOH, -CO H 2 , -N0 2 , -SH, -S0 2 CH 3 - S0 3 H,
  • alkylarylene is unsubstituted.
  • heterocycloalkyl includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.
  • R, R, R", R", and R" each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups.
  • aryl e.g., aryl substituted with 1-3 halogens
  • substituted or unsubstituted heteroaryl substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups.
  • each of the R groups is independently selected as are each R, R", R", and R"" group when more than one of these groups is present.
  • R and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7- membered ring.
  • -NR'R includes, but is not limited to, 1-pyrrolidinyl and 4- morpholinyl.
  • alkyl is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF 3 and -CH 2 CF 3 ) and acyl (e.g., - C(0)CH 3 , -C(0)CF 3 , -C(0)CH 2 OCH 3 , and the like).
  • haloalkyl e.g., -CF 3 and -CH 2 CF 3
  • acyl e.g., - C(0)CH 3 , -C(0)CF 3 , -C(0)CH 2 OCH 3 , and the like.
  • cycloalkylene, heterocycloalkylene, arylene, or heteroaryl ene may be depicted as
  • substituents on the ring rather than on a specific atom of a ring may be attached to any of the ring atoms (obeying the rules of chemical valency) and in the case of fused rings or spirocyclic rings, a substituent depicted as associated with one member of the fused rings or spirocyclic rings (a floating substituent on a single ring), may be a substituent on any of the fused rings or spirocyclic rings (a floating substituent on multiple rings).
  • the multiple substituents may be on the same atom, same ring, different atoms, different fused rings, different spirocyclic rings, and each substituent may optionally be different.
  • a point of attachment of a ring to the remainder of a molecule is not limited to a single atom (a floating substituent)
  • the attachment point may be any atom of the ring and in the case of a fused ring or spirocyclic ring, any atom of any of the fused rings or spirocyclic rings while obeying the rules of chemical valency.
  • a ring, fused rings, or spirocyclic rings contain one or more ring heteroatoms and the ring, fused rings, or spirocyclic rings are shown with one more floating substituents (including, but not limited to, points of attachment to the remainder of the molecule), the floating substituents may be bonded to the heteroatoms.
  • the ring heteroatoms are shown bound to one or more hydrogens (e.g. a ring nitrogen with two bonds to ring atoms and a third bond to a hydrogen) in the structure or formula with the floating substituent, when the heteroatom is bonded to the floating substituent, the substituent will be understood to replace the hydrogen, while obeying the rules of chemical valency.
  • Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups.
  • Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure.
  • the ring-forming substituents are attached to adjacent members of the base structure.
  • two ring-forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure.
  • the ring-forming substituents are attached to a single member of the base structure.
  • two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure.
  • the ring-forming substituents are attached to non- adjacent members of the base structure.
  • Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -T-C(0)-(CRR') q -U-, wherein T and U are
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH 2 )r-B-, wherein A and B are independently -CRR'-, -0-, - R-, -S-, -S(O) -, -S(0) 2 -, -S(0) 2 R'-, or a single bond, and r is an integer of from 1 to 4.
  • One of the single bonds of the new ring so formed may optionally be replaced with a double bond.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula - (CRR')s-X'- (C"R"R"')d-, where s and d are independently integers of from 0 to 3, and X' is - 0-, - R'-, -S-, -S(O)-, -S(0) 2 -, or -S(0) 2 R'-.
  • R, R', R", and R' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
  • heteroatom or "ring heteroatom” are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).
  • a "substituent group,” as used herein, means a group selected from the following moieties: (A) oxo,
  • halogen -CC1 3 , -CBr 3 , -CF 3 , -CI 3 ,-CN, -OH, -NH 2 , -COOH, -CO H 2 , -N0 2 , -SH, -S0 3 H, -S 0 4 H, -S0 2 H 2 , - HNH 2 , -O H 2 , - HC(0) HNH 2 , - HC(0) H 2 , - HS0 2 H,
  • -HC(0)H - HC(0)H, - HC(0)OH, - HOH, -OCCb, -OCF 3 , -OCBr 3 , -OCI 3 ,-OCHCl 2 , -OCHBr 2 , -OC HI 2 , -OCHF 2 , unsubstituted alkyl (e.g., Ci-C 8 alkyl, Ci-C 6 alkyl, or C1-C4 alkyl),
  • alkyl e.g., Ci-C 8 alkyl, Ci-C 6 alkyl, or C1-C4 alkyl
  • unsubstituted heteroalkyl e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • unsubstituted cycloalkyl e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C5-C6 cycloalkyl
  • unsubstituted heterocycloalkyl e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • unsubstituted aryl e.g., C 6 -Cio aryl, C10 aryl, or phenyl
  • unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl
  • halogen -CCI3, -CBr 3 , -CF 3 , -CI 3 ,-CN, -OH, -NH 2 , -COOH, -CO H 2 , -N0 2 , -SH, -S0 3 H, -S 0 4 H, -S0 2 H 2 , - HNH 2 , -O H 2 , - HC(0) H H 2 ,- HC(0) H 2 , - HS0 2 H,
  • -HC(0)H - HC(0)H, - HC(0)OH, - HOH, -OCCb, -OCF 3 , -OCBr 3 , -OCI 3 ,-OCHCl 2 , -OCHBr 2 , -OC HI 2 , -OCHF 2 , unsubstituted alkyl (e.g., Ci-C 8 alkyl, Ci-C 6 alkyl, or C1-C4 alkyl),
  • alkyl e.g., Ci-C 8 alkyl, Ci-C 6 alkyl, or C1-C4 alkyl
  • unsubstituted heteroalkyl e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • unsubstituted cycloalkyl e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C5-C6 cycloalkyl
  • unsubstituted heterocycloalkyl e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • unsubstituted aryl e.g., C 6 -Cio aryl, C10 aryl, or phenyl
  • unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl
  • unsubstituted alkyl e.g., Ci-C 8 alkyl, Ci-C 6 alkyl, or C1-C4 alkyl
  • unsubstituted heteroalkyl e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • unsubstituted cycloalkyl e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C5-C6 cycloalkyl
  • unsubstituted heterocycloalkyl e.g., 3 to 8 membere
  • halogen -CC1 3 , -CBr 3 , -CF 3 , -CI 3 ,-CN, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -S0 3 H, -SO4H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC (0)NHNH 2 , -NHC(0)NH 2 , -NHS0 2 H,
  • unsubstituted alkyl e.g., Ci-C 8 alkyl, Ci-C 6 alkyl, or C1-C4 alkyl
  • unsubstituted heteroalkyl e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • unsubstituted cycloalkyl e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl
  • unsubstituted heterocycloalkyl e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 member
  • a "size-limited substituent” or " size-limited substituent group,” as used herein, means a group selected from all of the substituents described above for a "substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C 6 -Cio aryl, and each substituted or unsubstituted heteroaryl
  • a "lower substituent” or " lower substituent group,” as used herein, means a group selected from all of the substituents described above for a "substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-Cs alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 3 - C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C 6 -Cio aryl, and each substituted or unsubstituted heteroaryl is a
  • each substituted group described in the compounds herein is substituted with at least one substituent group. More specifically, in some embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted
  • heterocycloalkyl substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene described in the compounds herein are substituted with at least one substituent group. In other embodiments, at least one or all of these groups are substituted with at least one size-limited substituent group. In other embodiments, at least one or all of these groups are substituted with at least one lower substituent group.
  • each substituted or unsubstituted alkyl may be a substituted or unsubstituted C1-C20 alkyl
  • each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl
  • each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl
  • each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered
  • each substituted or unsubstituted aryl is a substituted or unsubstituted C 6 - C10 aryl
  • each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl.
  • each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C20 alkylene
  • each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 20 membered
  • heteroalkylene each substituted or unsubstituted cycloalkylene is a substituted or
  • each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 8 membered heterocycloalkylene
  • each substituted or unsubstituted arylene is a substituted or unsubstituted C 6 -Cio arylene
  • each substituted or unsubstituted heteroaryl ene is a substituted or unsubstituted 5 to 10 membered
  • each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-Cs alkyl
  • each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl
  • each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl
  • each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-Cs alkyl
  • each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl
  • each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl
  • each substituted or unsubstituted or unsubstituted alkyl is a substituted or unsub
  • heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl
  • each substituted or unsubstituted aryl is a substituted or unsubstituted C 6 -Cio aryl
  • each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl.
  • each substituted or unsubstituted alkylene is a substituted or unsubstituted Ci-Cs alkylene
  • each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 8 membered heteroalkylene
  • unsubstituted cycloalkylene is a substituted or unsubstituted C3-C7 cycloalkylene
  • each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 7 membered heterocycloalkylene
  • each substituted or unsubstituted arylene is a substituted or unsubstituted C 6 -Cio arylene
  • each substituted or unsubstituted heteroaryl ene is a substituted or unsubstituted 5 to 9 membered heteroarylene.
  • the compound is a chemical species set forth in the Examples section, figures, or tables below.
  • a substituted moiety e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroaryl ene
  • is substituted with at least one substituent group wherein if the substituted moiety is substituted with a plurality of substituent groups, each substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of substituent groups, each substituent group is different.
  • a substituted moiety e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroaryl ene
  • is substituted with at least one size-limited substituent group wherein if the substituted moiety is substituted with a plurality of size-limited substituent groups, each size-limited substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of size-limited substituent groups, each size-limited substituent group is different.
  • a substituted moiety e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroaryl ene
  • is substituted with at least one lower substituent group wherein if the substituted moiety is substituted with a plurality of lower substituent groups, each lower substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of lower substituent groups, each lower substituent group is different.
  • a substituted moiety e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroaryl ene
  • the substituted moiety is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • Certain compounds of the present invention possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present invention.
  • the compounds of the present invention do not include those that are known in art to be too unstable to synthesize and/or isolate.
  • the present invention is meant to include compounds in racemic and optically pure forms.
  • Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.
  • isomers refers to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms.
  • tautomer refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.
  • structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention.
  • structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.
  • Analog or “analogue” is used in accordance with its plain ordinary meaning within Chemistry and Biology and refers to a chemical compound that is structurally similar to another compound (i.e., a so-called “reference” compound) but differs in composition, e.g., in the replacement of one atom by an atom of a different element, or in the presence of a particular functional group, or the replacement of one functional group by another functional group, or the absolute stereochemistry of one or more chiral centers of the reference compound. Accordingly, an analog is a compound that is similar or comparable in function and appearance but not in structure or origin to a reference compound. [0065] The terms "a” or "an,” as used in herein means one or more.
  • substituted with a[n] means the specified group may be substituted with one or more of any or all of the named substituents.
  • a group such as an alkyl or heteroaryl group
  • the group may contain one or more unsubstituted C1-C20 alkyls, and/or one or more unsubstituted 2 to 20 membered heteroalkyls.
  • R-substituted where a moiety is substituted with an R substituent, the group may be referred to as "R-substituted.” Where a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different. Where a particular R group is present in the description of a chemical genus (such as Formula (I)), a Roman alphabetic symbol may be used to distinguish each appearance of that particular R group. For example, where multiple R 13 substituents are present, each R 13 substituent may be
  • R 13A , R 13B , R 13C , R 13D , etc. distinguished as R 13A , R 13B , R 13C , R 13D , etc., wherein each of R 13A , R 13B , R 13C , R 13D , etc. is defined within the scope of the definition of R 13 and optionally differently.
  • a “covalent cysteine modifier moiety” as used herein refers to a substituent that is capable of reacting with the sulfhydryl functional group of a cysteine amino acid (e.g.
  • the covalent cysteine modifier moiety is typically electrophilic (e.g., an electrophilic group).
  • salts are meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p- tolyl sulfonic, citric, tartaric, oxalic, methanesulfonic, and the like.
  • inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic
  • salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19).
  • Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • the compounds of the present invention may exist as salts, such as with pharmaceutically acceptable acids.
  • the present invention includes such salts.
  • Non-limiting examples of such salts include hydrochlorides, hydrobromides, phosphates, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, proprionates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid, and quaternary ammonium salts (e.g. methyl iodide, ethyl iodide, and the like). These salts may be prepared by methods known to those skilled in the art.
  • the neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents.
  • the present invention provides compounds, which are in a prodrug form.
  • Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention.
  • Prodrugs of the compounds described herein may be converted in vivo after administration.
  • prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment, such as, for example, when contacted with a suitable enzyme or chemical reagent.
  • Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention.
  • Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
  • “Pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that aids the administration of an active agent to and absorption by a subject and can be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient.
  • “pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that aids the administration of an active agent to and absorption by a subject and can be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient.
  • pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer's, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like.
  • Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents
  • preparation is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it.
  • carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
  • a "prostaglandin reductase 1 inhibitor” and "PTGRl inhibitor” is a substance (e.g., oligonucleotide, composition, protein, or compound) that negatively affects (e.g. decreases) the activity or function of PTGRl relative to the activity or function of PTGRl in the absence of the inhibitor (e.g., wherein the PTGRl inhibitor binds PTGRl).
  • a "prostaglandin reductase 1 inhibitor compound” or “PTGRl inhibitor compound” refers to a compound (e.g. a compound described herein) that reduces the activity of PTGRl when compared to a control, such as absence of the compound or a compound with known inactivity.
  • polypeptide peptide
  • protein protein
  • amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymer.
  • a polypeptide, or a cell is "recombinant" when it is artificial or engineered, or derived from or contains an artificial or engineered protein or nucleic acid (e.g. non-natural or not wild type).
  • a polynucleotide that is inserted into a vector or any other heterologous location, e.g., in a genome of a recombinant organism, such that it is not associated with nucleotide sequences that normally flank the polynucleotide as it is found in nature is a recombinant polynucleotide.
  • a protein expressed in vitro or in vivo from a recombinant polynucleotide is an example of a recombinant polypeptide.
  • a polynucleotide sequence that does not appear in nature for example a variant of a naturally occurring gene, is recombinant.
  • an amino acid residue in a protein "corresponds" to a given residue when it occupies the same essential structural position within the protein as the given residue.
  • a selected residue in a selected protein corresponds to C239 of the human prostaglandin reductase 1 (PTGRl) when the selected residue occupies the same essential spatial or other structural relationship as C239 in human prostaglandin reductase 1 (PTGRl), for example in SEQ ID NO: l .
  • PTGRl human prostaglandin reductase 1
  • the position in the aligned selected protein aligning with C239 is said to correspond to C239.
  • a three dimensional structural alignment can also be used, e.g., where the structure of the selected protein is aligned for maximum correspondence with the human PTGRl protein (e.g., SEQ ID NO: 1) and the overall structures compared.
  • the human PTGRl protein e.g., SEQ ID NO: 1
  • an amino acid that occupies the same essential position as C239 in the structural model is said to correspond to the C239 residue.
  • Contacting is used in accordance with its plain ordinary meaning and refers to the process of allowing at least two distinct species (e.g. chemical compounds including biomolecules or cells) to become sufficiently proximal to react, interact or physically touch. It should be appreciated; however, the resulting reaction product can be produced directly from a reaction between the added reagents or from an intermediate from one or more of the added reagents that can be produced in the reaction mixture.
  • the term "contacting” may include allowing two species to react, interact, or physically touch, wherein the two species may be a compound as described herein and a protein or enzyme. In some embodiments contacting includes allowing a compound described herein to interact with a protein or enzyme that is involved in a signaling pathway.
  • activation activate
  • activating activator
  • activation means positively affecting (e.g. increasing) the concentration or levels of the protein relative to the concentration or level of the protein in the absence of the activator.
  • the terms may reference activation, or activating, sensitizing, or up-regulating signal transduction or enzymatic activity or the amount of a protein decreased in a disease.
  • activation may include, at least in part, partially or totally increasing stimulation, increasing or enabling activation, or activating, sensitizing, or up-regulating signal transduction or enzymatic activity or the amount of a protein associated with a disease (e.g., a protein which is decreased in a disease relative to a non-diseased control).
  • Activation may include, at least in part, partially or totally increasing stimulation, increasing or enabling activation, or activating, sensitizing, or up-regulating signal transduction or enzymatic activity or the amount of a protein.
  • inhibition means negatively affecting (e.g. decreasing) the activity or function of the protein relative to the activity or function of the protein in the absence of the inhibitor.
  • inhibition means negatively affecting (e.g.
  • inhibition refers to reduction of a disease or symptoms of disease. In embodiments, inhibition refers to a reduction in the activity of a particular protein target. Thus, inhibition includes, at least in part, partially or totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating, desensitizing, or down-regulating signal transduction or enzymatic activity or the amount of a protein. In embodiments, inhibition refers to a reduction of activity of a target protein resulting from a direct interaction (e.g. an inhibitor binds to the target protein). In
  • inhibition refers to a reduction of activity of a target protein from an indirect interaction (e.g. an inhibitor binds to a protein that activates the target protein, thereby preventing target protein activation).
  • a target protein from an indirect interaction
  • an inhibitor binds to a protein that activates the target protein, thereby preventing target protein activation.
  • the terms "prostaglandin reductase 1" and "PTGRl” and “LTB4DH” refer to a protein (including homologs, isoforms, and functional fragments thereof) with PTGRl activity.
  • the protein is involved in the inactivation of the chemotactic factor, leukotriene B4.
  • the protein specifically catalyzes the NADP+ dependent conversion of leukotriene B4 to 12- oxo-leukotriene B4.
  • the term includes any recombinant or naturally-occurring form of
  • PTGRl or variants thereof that maintain PTGRl activity (e.g. within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wildtype PTGRl).
  • the PTGRl protein encoded by the PTGRl gene has the amino acid sequence set forth in or corresponding to Entrez 22949, UniProt Q 14914 or RefSeq (protein)
  • the PTGRl gene has the nucleic acid sequence set forth in RefSeq (mRNA) NM 001146108.
  • the amino acid sequence or nucleic acid sequence is the sequence known at the time of filing of the present application.
  • the sequence corresponds to NP 001139580.1. In embodiments, the sequence corresponds to NM 001146108.1.
  • the PTGRl is a human PTGRl, such as a human cancer causing PTGRl .
  • the PTGRl protein encoded by the PTGRl gene has the amino acid sequence:
  • expression includes any step involved in the production of the polypeptide including, but not limited to, transcription, post-transcriptional modification, translation, post-translational modification, and secretion. Expression can be detected using conventional techniques for detecting protein (e.g., ELISA, Western blotting, flow cytometry, immunofluorescence, immunohistochemistry, etc.).
  • the terms "disease” or “condition” refer to a state of being or health status of a patient or subject capable of being treated with the compounds or methods provided herein.
  • the disease may be a cancer.
  • the disease may be stroke.
  • the disease may be an
  • cancer refers to human cancers and carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, etc., including solid and lymphoid cancers, kidney, breast, lung, bladder, colon, ovarian, prostate, pancreas, stomach, brain, head and neck, skin, uterine, testicular, glioma, esophagus, and liver cancer, including hepatocarcinoma, lymphoma, including B-acute lymphoblastic lymphoma, non-Hodgkin' s lymphomas (e.g., Burkitt' s, Small Cell, and Large Cell lymphomas), Hodgkin's lymphoma, leukemia (including AML, ALL, and CML), or multiple myeloma.
  • cancer refers to human cancers and carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, etc., including solid and lymphoid cancers, kidney,
  • cancer refers to all types of cancer, neoplasm or malignant tumors found in mammals (e.g. humans), including leukemia, carcinomas and sarcomas.
  • exemplary cancers that may be treated with a compound or method provided herein include brain cancer, glioma, glioblastoma, neuroblastoma, prostate cancer, colorectal cancer, pancreatic cancer, cervical cancer, gastric cancer, ovarian cancer, lung cancer, and cancer of the head.
  • Exemplary cancers that may be treated with a compound or method provided herein include cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head & neck, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus, Medulloblastoma, colorectal cancer, pancreatic cancer.
  • Additional examples include, Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, cancer, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, or prostate cancer.
  • leukemia refers broadly to progressive, malignant diseases of the blood- forming organs and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is generally clinically classified on the basis of (1) the duration and character of the disease-acute or chronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) the increase or non-increase in the number abnormal cells in the blood- leukemic or aleukemic (subleukemic).
  • Exemplary leukemias that may be treated with a compound or method provided herein include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia,
  • sarcoma generally refers to a tumor which is made up of a substance like the embryonic connective tissue and is generally composed of closely packed cells embedded in a fibrillar or homogeneous substance.
  • Sarcomas that may be treated with a compound or method provided herein include a chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sar
  • melanoma is taken to mean a tumor arising from the melanocytic system of the skin and other organs.
  • Melanomas that may be treated with a compound or method provided herein include, for example, acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungal melanoma, or superficial spreading melanoma.
  • carcinoma refers to a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases.
  • exemplary carcinomas that may be treated with a compound or method provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid
  • TNBC triple negative breast cancer
  • ER estrogen receptor
  • PR progesterone receptor
  • Her2/neu Her2/neu
  • TNBC cells overexpress epidermal growth factor receptor (EGFR) or transmembrane glycoprotein NMB (GPNMB). TNBC may be correlated with germline mutations within the BRCA1 and BRCA2 genes.
  • the terms “treating”, or “treatment” refers to any indicia of success in the therapy or amelioration of an injury, disease, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of
  • the treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and/or a psychiatric evaluation.
  • the term "treating" and conjugations thereof, may include prevention of an injury, pathology, condition, or disease.
  • treating is preventing. In embodiments, treating does not include preventing. In embodiments, the treating or treatment is no prophylactic treatment.
  • Patient or “subject in need thereof refers to a living organism suffering from or prone to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein.
  • Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammalian animals.
  • a patient is human.
  • a "effective amount” is an amount sufficient for a compound to accomplish a stated purpose relative to the absence of the compound (e.g. achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce a signaling pathway, or reduce one or more symptoms of a disease or condition).
  • An example of an “effective amount” is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, which could also be referred to as a "therapeutically effective amount.”
  • a “reduction” of a symptom or symptoms means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s).
  • a “prophylactically effective amount” of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms.
  • the full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses.
  • a prophylactically effective amount may be administered in one or more administrations.
  • An “activity decreasing amount,” as used herein, refers to an amount of antagonist required to decrease the activity of an enzyme relative to the absence of the antagonist.
  • a “function disrupting amount,” as used herein, refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of the antagonist. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).
  • the therapeutically effective amount can be initially determined from cell culture assays.
  • Target concentrations will be those
  • therapeutically effective amounts for use in humans can also be determined from animal models.
  • a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals.
  • the dosage in humans can be adjusted by monitoring compounds effectiveness and adjusting the dosage upwards or downwards, as described above. Adjusting the dose to achieve maximal efficacy in humans based on the methods described above and other methods is well within the capabilities of the ordinarily skilled artisan.
  • Dosages may be varied depending upon the requirements of the patient and the compound being employed. The dose administered to a patient, in the context of the present invention should be sufficient to effect a beneficial therapeutic response in the patient over time.
  • the size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. Dosage amounts and intervals can be adjusted individually to provide levels of the administered compound effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the individual's disease state.
  • administering means oral administration, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject.
  • Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal) compatible with the preparation.
  • Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial.
  • Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc.
  • composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies.
  • the compounds of the invention can be administered alone or can be
  • compositions of the present invention can be delivered transdermally, by a topical route, or formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.
  • a cell can be identified by well-known methods in the art including, for example, presence of an intact membrane, staining by a particular dye, ability to produce progeny or, in the case of a gamete, ability to combine with a second gamete to produce a viable offspring.
  • Cells may include prokaryotic and eukaroytic cells.
  • Prokaryotic cells include but are not limited to bacteria.
  • Eukaryotic cells include but are not limited to yeast cells and cells derived from plants and animals, for example mammalian, insect ⁇ e.g., spodoptera) and human cells. Cells may be useful when they are naturally nonadherent or have been treated not to adhere to surfaces, for example by trypsinization.
  • Control or "control experiment” is used in accordance with its plain ordinary meaning and refers to an experiment in which the subjects or reagents of the experiment are treated as in a parallel experiment except for omission of a procedure, reagent, or variable of the experiment. In some instances, the control is used as a standard of comparison in evaluating experimental effects. In some embodiments, a control is the measurement of the activity of a protein in the absence of a compound as described herein (including embodiments and examples).
  • a PTGRl associated disease modulator is a compound that reduces the severity of one or more symptoms of a disease associated with PTGRl (e.g. cancer).
  • a PTGRl modulator is a compound that increases or decreases the activity or function or level of activity or level of function of PTGRl .
  • modulate is used in accordance with its plain ordinary meaning and refers to the act of changing or varying one or more properties. “Modulation” refers to the process of changing or varying one or more properties. For example, as applied to the effects of a modulator on a target protein, to modulate means to change by increasing or decreasing a property or function of the target molecule or the amount of the target molecule.
  • a disease e.g. a protein associated disease, a cancer associated with PTGRl activity, PTGRl associated cancer, PTGRl associated disease
  • the disease e.g. cancer
  • a symptom of the disease is caused by (in whole or inpart) the substance or substance activity or function.
  • a cancer associated with PTGRl activity or function may be a cancer that results (entirely or partially) from aberrant PTGRl function (e.g.
  • a cancer associated with PTGRl activity or function or a PTGRl associated cancer may be treated with a PTGRl modulator or PTGRl inhibitor, in the instance where PTGRl activity or function (e.g. signaling pathway activity) causes the cancer.
  • aberrant refers to different from normal. When used to describe enzymatic activity or protein function, aberrant refers to activity or function that is greater or less than a normal control or the average of normal non-diseased control samples. Aberrant activity may refer to an amount of activity that results in a disease, wherein returning the aberrant activity to a normal or non-disease-associated amount (e.g. by administering a compound or using a method as described herein), results in reduction of the disease or one or more disease symptoms.
  • signaling pathway refers to a series of interactions between cellular and optionally extra-cellular components (e.g. proteins, nucleic acids, small molecules, ions, lipids) that conveys a change in one component to one or more other components, which in turn may convey a change to additional components, which is optionally propagated to other signaling pathway components.
  • extra-cellular components e.g. proteins, nucleic acids, small molecules, ions, lipids
  • binding of a PTGRl protein with a compound as described herein may reduce the interactions between the PTGRl protein and downstream effectors or signaling pathway components, resulting in changes in cell growth, proliferation, or survival.
  • electrophilic group is used in accordance with its plain ordinary meaning and refers to a chemical group that is electrophilic. In embodiments, the
  • electrophilic group is an "electrophilic chemical moiety", which is used in accordance with its plain ordinary chemical meaning and refers to a monovalent chemical group that is electrophilic.
  • the electrophilic group is a covalent cysteine modifier moiety.
  • the electrophilic group is divalent.
  • the electrophilic group is .
  • the reacted electrophilic group is
  • nucleophilic chemical group is used in accordance with its plain ordinary chemical meaning and refers to a chemical group (e.g., monovalent chemical group) that is nucleophilic.
  • Nucleic acid refers to nucleotides (e.g., deoxyribonucleotides or ribonucleotides) and polymers thereof in either single-, double- or multiple-stranded form, or complements thereof.
  • polynucleotide e.g., oligonucleotide
  • oligo oligo
  • nucleotide refers, in the usual and customary sense, to a linear sequence of nucleotides.
  • nucleotide refers, in the usual and customary sense, to a single unit of a polynucleotide, i.e., a monomer.
  • Nucleotides can be ribonucleotides, deoxyribonucleotides, or modified versions thereof.
  • Examples of polynucleotides contemplated herein include single and double stranded DNA, single and double stranded RNA, and hybrid molecules having mixtures of single and double stranded DNA and RNA.
  • Examples of nucleic acid, e.g. polynucleotides contemplated herein include any types of RNA, e.g. mRNA, siRNA, miRNA, and guide RNA and any types of DNA, genomic DNA, plasmid DNA, and minicircle DNA, and any fragments thereof.
  • nucleic acids can be linear or branched.
  • nucleic acids can be a linear chain of nucleotides or the nucleic acids can be branched, e.g., such that the nucleic acids comprise one or more arms or branches of nucleotides.
  • the branched nucleic acids are repetitively branched to form higher ordered structures such as dendrimers and the like.
  • Nucleic acids can include one or more reactive moieties.
  • the term reactive moiety includes any group capable of reacting with another molecule, e.g., a nucleic acid or polypeptide through covalent, non-covalent or other interactions.
  • the nucleic acid can include an amino acid reactive moiety that reacts with an amio acid on a protein or polypeptide through a covalent, non-covalent or other interaction.
  • nucleic acids containing known nucleotide analogs or modified backbone residues or linkages which are synthetic, naturally occurring, and non- naturally occurring, which have similar binding properties as the reference nucleic acid, and which are metabolized in a manner similar to the reference nucleotides.
  • Examples of such analogs include, include, without limitation, phosphodiester derivatives including, e.g., phosphoramidate, phosphorodiamidate, phosphorothioate (also known as phosphothioate having double bonded sulfur replacing oxygen in the phosphate), phosphorodithioate, phosphonocarboxylic acids, phosphonocarboxylates, phosphonoacetic acid, phosphonoformic acid, methyl phosphonate, boron phosphonate, or O-methylphosphoroamidite linkages (see Eckstein, OLIGONUCLEOTIDES AND ANALOGUES: A PRACTICAL APPROACH, Oxford University Press) as well as modifications to the nucleotide bases such as in 5-methyl cytidine or pseudouridine.; and peptide nucleic acid backbones and linkages.
  • phosphodiester derivatives including, e.g., phosphoramidate, phosphorodiamidate, phosphorothioate (also known as phospho
  • nucleic acids include those with positive backbones; non-ionic backbones, modified sugars, and non-ribose backbones (e.g. phosphorodiamidate morpholino oligos or locked nucleic acids (LNA) as known in the art), including those described in U.S. Patent Nos. 5,235,033 and 5,034,506, and Chapters 6 and 7, ASC Symposium Series 580, CARBOHYDRATE MODIFICATIONS IN ANTISENSE RESEARCH, Sanghui & Cook, eds. Nucleic acids containing one or more carbocyclic sugars are also included within one definition of nucleic acids.
  • LNA locked nucleic acids
  • Modifications of the ribose-phosphate backbone may be done for a variety of reasons, e.g., to increase the stability and half-life of such molecules in physiological environments or as probes on a biochip.
  • Mixtures of naturally occurring nucleic acids and analogs can be made; alternatively, mixtures of different nucleic acid analogs, and mixtures of naturally occurring nucleic acids and analogs may be made.
  • the internucleotide linkages in DNA are phosphodiester, phosphodiester derivatives, or a combination of both.
  • Nucleic acids can include nonspecific sequences. As used herein, the term
  • nonspecific sequence refers to a nucleic acid sequence that contains a series of residues that are not designed to be complementary to or are only partially complementary to any other nucleic acid sequence.
  • a nonspecific nucleic acid sequence is a sequence of nucleic acid residues that does not function as an inhibitory nucleic acid when contacted with a cell or organism.
  • an "antisense nucleic acid” as referred to herein is a nucleic acid (e.g., DNA or RNA molecule) that is complementary to at least a portion of a specific target nucleic acid (e.g., a nucleic acid coding for one or more amino acids corresponding to P48, M124, T128, A149, A153, V154, N217, C239, Y245, V271, or V272 of SEQ ID NO: l) and is capable of reducing transcription of the target nucleic acid (e.g. mRNA from DNA), reducing the translation of the target nucleic acid (e.g. mRNA), altering transcript splicing (e.g.
  • a specific target nucleic acid e.g., a nucleic acid coding for one or more amino acids corresponding to P48, M124, T128, A149, A153, V154, N217, C239, Y245, V271, or V272 of SEQ ID
  • antisense nucleic acids are generally between 15 and 25 bases in length.
  • antisense nucleic acids are capable of hybridizing to (e.g. selectively hybridizing to) a target nucleic acid (e.g., a nucleic acid coding for one or more amino acids corresponding to P48, M124, T128, A149, A153, V154, N217, C239, Y245, V271, or V272 of SEQ ID NO: 1).
  • the antisense nucleic acid hybridizes to the target nucleic acid (e.g. a nucleic acid coding for one or more amino acids corresponding to P48, M124, T128, A149, A153, V154, N217, C239, Y245, V271, or V272 of SEQ ID NO: 1) in vitro.
  • the antisense nucleic acid hybridizes to the target nucleic acid (e.g. a nucleic acid coding for one or more amino acids corresponding to P48, M124, T128, A149, A153, V154, N217, C239, Y245, V271, or V272 of SEQ ID NO: l) in a cell.
  • the target nucleic acid e.g. a nucleic acid coding for one or more amino acids corresponding to P48, M124, T128, A149, A153, V154, N217, C239, Y245, V271, or V272 of SEQ ID NO:
  • the antisense nucleic acid hybridizes to the target nucleic acid (e.g. a nucleic acid coding for one or more amino acids corresponding to P48, M124, T128, A149, A153, V154, N217, C239, Y245, V271, or V272 of SEQ ID NO: 1) in an organism.
  • the target nucleic acid e.g. a nucleic acid coding for one or more amino acids corresponding to P48, M124, T128, A149, A153, V154, N217, C239, Y245, V271, or V272 of SEQ ID NO: 1
  • the antisense nucleic acid hybridizes to the target nucleic acid (e.g. a nucleic acid coding for a nucleic acid coding for one or more amino acids corresponding to P48, M124, T128, A149, A153, V154, N217, C239, Y245, V271, or V272 of SEQ ID NO: 1) under physiological conditions.
  • Antisense nucleic acids may comprise naturally occurring nucleotides or modified nucleotides such as, e.g., phosphorothioate, methylphosphonate, and -anomeric sugar-phosphate, backbonemodified nucleotides.
  • the antisense nucleic acids hybridize to the corresponding RNA (e.g., a nucleic acid coding for one or more amino acids corresponding to P48, M124, T128, A149, A153, V154, N217, C239, Y245, V271, or V272 of SEQ ID NO: l) forming a double- stranded molecule.
  • RNA e.g., a nucleic acid coding for one or more amino acids corresponding to P48, M124, T128, A149, A153, V154, N217, C239, Y245, V271, or V272 of SEQ ID NO: l
  • the antisense nucleic acids interfere with the endogenous behavior of the RNA (e.g., a nucleic acid coding for one or more amino acids corresponding to P48, M124, T128, A149, A153, V154, N217, C239, Y245, V271, or V272 of SEQ ID NO: l) and inhibit its function relative to the absence of the antisense nucleic acid. Furthermore, the double- stranded molecule may be degraded via the RNAi pathway.
  • the use of antisense methods to inhibit the in vitro translation of genes is well known in the art (Marcus-Sakura, Anal.
  • Antisense molecules which bind directly to the DNA may be used.
  • Antisense nucleic acids may be single or double stranded nucleic acids.
  • Non- limiting examples of antisense nucleic acids include siRNAs (including their derivatives or pre-cursors, such as nucleotide analogs), short hairpin RNAs (shRNA), micro RNAs (miRNA), saRNAs (small activating RNAs) and small nucleolar RNAs (snoRNA) or certain of their derivatives or pre-cursors.
  • complement refers to a nucleotide (e.g., RNA or DNA) or a sequence of nucleotides capable of base pairing with a complementary nucleotide or sequence of nucleotides.
  • a complement may include a sequence of nucleotides that base pair with corresponding complementary nucleotides of a second nucleic acid sequence.
  • nucleotides of a complement may partially or completely match the nucleotides of the second nucleic acid sequence. Where the nucleotides of the complement completely match each nucleotide of the second nucleic acid sequence, the complement forms base pairs with each nucleotide of the second nucleic acid
  • nucleotides of the complement partially match the nucleotides of the second nucleic acid sequence only some of the nucleotides of the complement form base pairs with nucleotides of the second nucleic acid sequence.
  • complementary sequences include coding and a non-coding sequences, wherein the non-coding sequence contains complementary nucleotides to the coding sequence and thus forms the complement of the coding sequence.
  • complementary sequences are sense and antisense sequences, wherein the sense sequence contains complementary nucleotides to the antisense sequence and thus forms the complement of the antisense sequence.
  • the complementarity of sequences may be partial, in which only some of the nucleic acids match according to base pairing, or complete, where all the nucleic acids match according to base pairing.
  • two sequences that are complementary to each other may have a specified percentage of nucleotides that are the same (i.e., about 60% identity, preferably 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%), 98%), 99%), or higher identity over a specified region).
  • the term "antibody” refers to a polypeptide encoded by an immunoglobulin gene or functional fragments thereof that specifically binds and recognizes an antigen.
  • the recognized immunoglobulin genes include the kappa, lambda, alpha, gamma, delta, epsilon, and mu constant region genes, as well as the myriad immunoglobulin variable region genes.
  • Light chains are classified as either kappa or lambda.
  • Heavy chains are classified as gamma, mu, alpha, delta, or epsilon, which in turn define the immunoglobulin classes, IgG, IgM, IgA, IgD and IgE, respectively.
  • An exemplary immunoglobulin (antibody) structural unit comprises a tetramer.
  • Each tetramer is composed of two identical pairs of polypeptide chains, each pair having one "light” (about 25 kDa) and one "heavy" chain (about 50-70 kDa).
  • the N-terminus of each chain defines a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition.
  • variable heavy chain refers to the variable region of an immunoglobulin heavy chain, including an Fv, scFv , dsFv or Fab; while the terms “variable light chain,” “VL” or “VL” refer to the variable region of an immunoglobulin light chain, including of an Fv, scFv , dsFv or Fab.
  • antibody functional fragments include, but are not limited to, complete antibody molecules, antibody fragments, such as Fv, single chain Fv (scFv), complementarity determining regions (CDRs), VL (light chain variable region), VH (heavy chain variable region), Fab, F(ab)2' and any combination of those or any other functional portion of an immunoglobulin peptide capable of binding to target antigen (see, e.g., FUNDAMENTAL IMMUNOLOGY (Paul ed., 4th ed. 2001).
  • various antibody fragments can be obtained by a variety of methods, for example, digestion of an intact antibody with an enzyme, such as pepsin; or de novo synthesis.
  • Antibody fragments are often synthesized de novo either chemically or by using recombinant DNA methodology.
  • the term antibody includes antibody fragments either produced by the modification of whole antibodies, or those synthesized de novo using recombinant DNA methodologies (e.g., single chain Fv) or those identified using phage display libraries (see, e.g., McCafferty et al, (1990) Nature 348:552).
  • the term "antibody” also includes bivalent or bispecific molecules, diabodies, triabodies, and tetrabodies. Bivalent and bispecific molecules are described in, e.g., Kostelny et al. (1992) J. Immunol.
  • Percentage of sequence identity is determined by comparing two optimally aligned sequences over a comparison window, wherein the portion of the polynucleotide or polypeptide sequence in the comparison window may comprise additions or deletions (i.e., gaps) as compared to the reference sequence (which does not comprise additions or deletions) for optimal alignment of the two sequences. The percentage is calculated by determining the number of positions at which the identical nucleic acid base or amino acid residue occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison and multiplying the result by 100 to yield the percentage of sequence identity.
  • nucleic acids or polypeptide sequences refer to two or more sequences or subsequences that are the same or have a specified percentage of amino acid residues or nucleotides that are the same (i.e., about 60% identity, preferably 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%), 96%), 97%), 98%, 99%, or higher identity over a specified region, when compared and aligned for maximum correspondence over a comparison window or designated region) as measured using a BLAST or BLAST 2.0 sequence comparison algorithms with default parameters described below, or by manual alignment and visual inspection (see, e.g., NCBI web site http://www.ncbi.nlm.nih.gov/BLAST/ or the like).
  • sequences are then said to be “substantially identical.”
  • This definition also refers to, or may be applied to, the compliment of a test sequence.
  • the definition also includes sequences that have deletions and/or additions, as well as those that have substitutions.
  • the preferred algorithms can account for gaps and the like.
  • identity exists over a region that is at least about 25 amino acids or nucleotides in length, or more preferably over a region that is 50-100 amino acids or nucleotides in length.
  • irreversible covalent bond is used in accordance with its plain ordinary meaning in the art and refers to the resulting association between atoms or molecules of (e.g., electrophilic chemical moiety (an electrophilic group such as a covalent cysteine modifier moiety) and nucleophilic moiety) wherein the probability of dissociation is low.
  • electrophilic chemical moiety an electrophilic group such as a covalent cysteine modifier moiety
  • nucleophilic moiety an electrophilic group such as a covalent cysteine modifier moiety
  • the irreversible covalent bond does not easily dissociate under normal biological conditions.
  • the irreversible covalent bond is formed through a chemical reaction between two species (e.g., electrophilic chemical moiety and nucleophilic moiety).
  • Anti-cancer agent and “anticancer agent” are used in accordance with their plain ordinary meaning and refers to a composition (e.g. compound, drug, antagonist, inhibitor, modulator) having antineoplastic properties or the ability to inhibit the growth or proliferation of cells.
  • an anti-cancer agent is a chemotherapeutic.
  • an anti-cancer agent is an agent identified herein having utility in methods of treating cancer.
  • an anti-cancer agent is an agent approved by the FDA or similar regulatory agency of a country other than the USA, for treating cancer. Examples of anti-cancer agents include, but are not limited to, MEK (e.g.
  • MEKl, MEK2, or MEKl and MEK2 inhibitors e.g. XL518, CI-1040, PD035901, selumetinib/ AZD6244, GSK1120212/ trametinib, GDC-0973, ARRY-162, ARRY-300, AZD8330, PD0325901, U0126, PD98059, TAK-733, PD318088, AS703026, BAY 869766
  • alkylating agents e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, uramustine, thiotepa, nitrosoureas, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, meiphalan), ethylenimine and methylmelamines (e.g., hex
  • adecypenol adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine;
  • amidox amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti- dorsalizing morphogenetic protein- 1 ; antiandrogen, prostatic carcinoma; antiestrogen;
  • antineoplaston antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1 ; axinastatin 2; axinastatin 3; azasetron; azatoxin;
  • azatyrosine baccatin III derivatives; balanol; batimastat; BCR/ABL antagonists;
  • benzochlorins benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine;
  • calcipotriol calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine;
  • carboxamide-amino-triazole carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4;
  • combretastatin analogue conagenin; crambescidin 816; crisnatol; cryptophycin 8;
  • cryptophycin A derivatives curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone;
  • didemnin B didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; 9-dioxamycin; diphenyl spiromustine; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin
  • epirubicin epristeride
  • estramustine analogue epristeride
  • estrogen agonists epristeride
  • estrogen antagonists epristeride
  • estramustine analogue epristeride
  • estrogen agonists epristeride
  • estrogen antagonists epristeride
  • etanidazole etoposide phosphate; exemestane; fadrozole; trasrabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin
  • hydrochloride forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin;
  • gallium nitrate galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulant peptides; insulin-like growth factor- 1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; lein
  • leuprolide+estrogen+progesterone leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine;
  • marimastat masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor;
  • mifepristone miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1 -based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N- substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid;
  • octreotide okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; palauamine;
  • palmitoylrhizoxin pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine;
  • pegaspargase peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B;
  • plasminogen activator inhibitor platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor;
  • protein kinase C inhibitors microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpunns; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylerie conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone B 1 ; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A;
  • oligonucleotides oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen-binding protein; sizofuran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D;
  • spiromustine splenopentin
  • spongistatin 1 squalamine
  • stem cell inhibitor stem-cell division inhibitors
  • stipiamide stem-cell division inhibitors
  • stromelysin inhibitors sulfinosine
  • superactive vasoactive intestinal peptide antagonist suradista; suramin; swainsonine; synthetic glycosaminoglycans;
  • tallimustine tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide;
  • thrombopoietin mimetic thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine;
  • triciribine trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors;
  • tyrphostins UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; zinostatin stimalamer, Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine;
  • azotomycin batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan;
  • cactinomycin calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride;
  • decitabine dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine;
  • fadrozole hydrochloride adrozole hydrochloride
  • fenretinide adrozole hydrochloride
  • floxuridine adrozole hydrochloride
  • fludarabine phosphate adrozole hydrochloride
  • fluorouracil fluorocitabine
  • fosquidone fostriecin sodium
  • gemcitabine gemcitabine hydrochloride
  • hydroxyurea idarubicin hydrochloride
  • ifosfamide iimofosine
  • interleukin II interleukin II
  • interferon alfa-2a including recombinant interleukin II, or rlL.sub.2
  • interferon alfa-2a interferon alfa-2b
  • interferon alfa-nl interferon alfa-n3
  • interferon beta- la interferon beta- la
  • interferon gamma-lb interferon gamma-lb
  • iproplatin irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate;
  • melphalan menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazoie;
  • Taxotere.TM compounds comprising the taxane skeleton, Erbulozole (i.e. R-
  • Dolastatin 10 i.e. DLS-10 and NSC-376128
  • Mivobulin isethionate i.e. as CI-980
  • Vincristine i.e. as NSC-639829
  • Discodermolide i.e. as NVP-XX-A-296
  • ABT-751 Abbott, i.e. E-7010
  • Altorhyrtins e.g. Altorhyrtin A and Altorhyrtin C
  • Spongistatins e.g.
  • Epothilones e.g. Epothilone A, Epothilone B, Epothilone C (i.e.
  • Epothilone A or dEpoA desoxyepothilone A or dEpoA
  • Epothilone D i.e. KOS-862, dEpoB, and desoxyepothilone B
  • Epothilone E Epothilone F
  • Epothilone B N-oxide Epothilone A N-oxide
  • 16-aza- epothilone B Epothilone A N-oxide
  • 21-aminoepothilone B i.e. BMS-310705
  • 21 -hydroxy epothilone D i.e.
  • WS-9885B GS-164 (Takeda), GS- 198 (Takeda), KAR-2 (Hungarian Academy of Sciences), BSF-223651 (BASF, i.e. ILX-651 and LU-223651), SAH-49960 (Lilly/Novartis), SDZ-268970 (Lilly/Novartis), AM-97 (Armad/Kyowa Hakko), AM-132 (Armad), AM-138 (Armad/Kyowa Hakko), IDN-5005
  • Cryptophycin 52 i.e. LY-355703
  • AC-7739 Ajinomoto, i.e. AVE-8063A and CS- 39.HC1
  • AC-7700 Ajinomoto, i.e. AVE-8062, AVE-8062A, CS-39-L-Ser.HCl, and RPR- 258062 A
  • Vitilevuamide Tubulysin A, Canadensol, Centaureidin (i.e. NSC- 106969), T- 138067 (Tularik, i.e. T-67, TL-138067 and TI-138067), COBRA-1 (Parker Hughes Institute, i.e.
  • DDE-261 and WHI-261 H10 (Kansas State University), H16 (Kansas State University), Oncocidin Al (i.e. BTO-956 and DFME), DDE-313 (Parker Hughes Institute), Fijianolide B, Laulimalide, SPA-2 (Parker Hughes Institute), SPA-1 (Parker Hughes Institute, i.e. SPIKET- P), 3-IAABU (Cytoskeleton/Mt. Yale School of Medicine, i.e. MF-569), Narcosine (also known as NSC-5366), Nascapine, D-24851 (Asta Medica), A-105972 (Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton/Mt.
  • NSCL-96F03-7 D-68838 (Asta Medica), D-68836 (Asta Medica), Myoseverin B, D-43411 (Zentaris, i.e. D-81862), A- 289099 (Abbott), A-318315 (Abbott), HTI-286 (i.e.
  • SPA-110, trifluoroacetate salt) (Wyeth), D-82317 (Zentaris), D-82318 (Zentaris), SC-12983 (NCI), Resverastatin phosphate sodium, BPR-OY-007 (National Health Research Institutes), and SSR-250411 (Sanofi)), steroids (e.g., dexamethasone), finasteride, aromatase inhibitors, gonadotropin-releasing hormone agonists (GnRH) such as goserelin or leuprolide, adrenocorticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethlystilbestrol, ethinyl estradiol), antiestrogen (e.g., tamoxifen), androgens (e.
  • Prostaglandin reductase 1 (PTGR1) activity refers to the biological activity of the protein.
  • Prostaglandin reductase 1 (PTGR1) activity may be quantified by measuring the rate of cell division, cell survival, or cell migration, measuring mitochondrial respiration, measuring the levels or activity of 15-keto-prostaglandin relative to a control (e.g., the absence of the inhibitor), measuring the levels or activity of leukotriene B4 relative to a control (e.g., the absence of the inhibitor), measuring the level of activity of carnitine palmitoyltransferase 1 (CPT1) (e.g, compared to a control such as absence of the composition), or quantifying the binding of NADP+ to PTGR1.
  • CPT1 carnitine palmitoyltransferase 1
  • the PTGR1 activity is reducing the level of 15-keto-prostaglandin or leukotriene B4. In embodiments, the PTGR1 activity is reducing the level of 15-keto-prostaglandin. In embodiments, the PTGRl activity is reducing the level of leukotriene B4. In embodiments, the PTGRl activity is reducing the activity of 15-keto-prostaglandin. In embodiments, the PTGRl activity is reducing the activity of leukotriene B4. In embodiments, the PTGRl activity is binding NADP+. In embodiments, the PTGRl activity is converting leukotriene B4 to 12-oxo- leukotriene B4. In embodiments, a reduction in PTGRl activity results in a reduction in the levels of 12-oxo-leukotriene B4.
  • prostaglandin reductase 1 (PTGRl) protein- prostaglandin reductase 1 (PTGRl) inhibitor complex refers to a prostaglandin reductase 1 (PTGRl) protein bonded (e.g., covalently bonded) to a prostaglandin reductase 1 (PTGRl) inhibitor (e.g., a compound described herein).
  • R 1 is independently halogen, -CXS, -CHX ⁇ , -CH2X 1 , -OCX ⁇ , - OCH2X 1 , -OCHX ⁇ , -CN, -SOniR 1D , -SO v i R 1A R 1B , - HC(0) R 1A R 1B , -N(0) m i, - R 1A R 1B , -C(0)R 1C , -C(0)-OR lc , -C(0) R 1A R 1B , -OR 1D , - R 1A S0 2 R 1D , - R 1A C(0)R 1C , - R 1A C(0)0 R 1C , - R 1A OR lc , -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsub
  • heterocycloalkyl substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl
  • two adjacent R 1 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • the symbol zl is an integer from 0 to 5.
  • R 2 is independently halogen, -CX 2 3 , -CHX 2 2 , -CH 2 X 2 , -OCX 2 3 , -
  • R , -NR OR , -N 3 substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
  • heterocycloalkyl substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl
  • two adjacent R 2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • the symbol z2 is an integer from 0 to 5.
  • R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , and R 2D is independently
  • R 1A and R 1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R 2A and R 2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.
  • Each X, X 1 , and X 2 is independently -F, -CI, -Br, or -I.
  • the symbols nl and n2 are independently an integer from 0 to 4.
  • the symbols ml, m2, vl, and v2 are independently an integer from 1 to 2.
  • the compound is not licochalcone A. [0130] In embodiments, the compound has the formula:
  • R u , R 1 2 , R , R 1 4 , and R 1 5 are independently hydrogen, halogen, -CX ⁇ , -CHX ⁇ , -
  • heterocycloalkyl substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 2 ⁇ R 2 2 , R 2 3 , R 2 4 , and R 2 5 are independently hydrogen, halogen, -CX 2 3 , -CHX 2 2 , - CH 2 X 2 , -OCX 2 3 , -
  • the compound has the formula:
  • R 1 2 , R 1 3 , R 1 5 , and R 2 3 are as described herein.
  • R 1 2 is independently substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl. In embodiments, R 1 2 is independently unsubstituted alkyl. In embodiments, R 1 2 is independently unsubstituted Ci-Cs alkyl. In embodiments, R 1 2 is independently unsubstituted C1-C5 alkyl. In embodiments, R 1 2 is independently unsubstituted C1-C5 alkenyl.
  • R 1 2 has the formula [0135]
  • R 1 3 is independently -OCX ⁇ , -OCH2X 1 , -OCHX ⁇ , -OR 1D , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
  • R 1 3 is independently -OR 1D . In embodiments, R 1 3 is independently -OR 1D . In embodiments, R 1 3 is independently -OH. In embodiments, R 1 3 is independently not -OH. In embodiments, R 1 3 is independently not hydrogen. [0136] In embodiments, R 1 5 is independently -OCX ⁇ , -OCH2X 1 , -OCHX ⁇ , -OR 1D , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. In
  • R 1 5 is independently -OR 1D . In embodiments, R 1 5 is independently -OCH3. In embodiments, R 1 5 is independently not -OH. In embodiments, R 1 5 is independently not hydrogen. [0137] In embodiments, R 1D is independently hydrogen, -CX 3 , -CHX 2 , -CH 2 X, substituted or unsubstituted alkyl. In embodiments, R 1D is independently hydrogen or substituted or unsubstituted Ci-Cs alkyl. In embodiments, R 1D is independently hydrogen or unsubstituted C1-C4 alkyl. In embodiments, R 1D is independently unsubstituted C1-C2 alkyl.
  • R 2 3 is independently -OCX 2 3 , -OCH2X 2 , -OCHX 2 2 , -OR 2D , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
  • R 2 3 is independently -OR 2D . In embodiments, R 2 3 is independently -OR 2D . In embodiments, R 2 3 is independently -OH. In embodiments, R 2 3 is independently not -OH. In embodiments, R 2 3 is independently not hydrogen. In embodiments, R 2 1 is independently not -OH. In embodiments, R 2 1 is independently not hydrogen. In embodiments, R 2 2 is independently not -OH. In embodiments, R 2 2 is independently not hydrogen. In
  • R 2 5 is independently not -OH. In embodiments, R 2 5 is independently not hydrogen. In embodiments, R 2 4 is independently not -OH. In embodiments, R 2 4 is independently not hydrogen. In embodiments, R 2 2 is independently not unsubstituted alkyl. In embodiments, R 2 2 is independently not unsubstituted Ci-C 6 alkyl. In embodiments, R 2 2 is independently not unsubstituted C2-C6 alkenyl. In embodiments, R 2 2 is independently not unsubstituted C4-C6 alkenyl. In embodiments, R 2 4 is independently not unsubstituted alkyl. In embodiments, R 2 4 is independently not unsubstituted Ci-C 6 alkyl. In embodiments, R 2 4 is independently not unsubstituted C2-C6 alkenyl. In embodiments, R 2 4 is independently not unsubstituted C4-C6 alkenyl.
  • R 2D is independently hydrogen, -CX3, -CHX 2 , -CH 2 X, substituted or unsubstituted alkyl. In embodiments, R 2D is independently hydrogen or substituted or unsubstituted Ci-Cs alkyl.
  • R 1 2 is independently substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl
  • R 1 3 is independently -OCX ⁇ , - OCH2X 1 , -OCHX ⁇ , -OR 1D , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl
  • R 1 5 is independently -OCX ⁇ , -OCH2X 1 , -OCHX ⁇ , -OR 1D , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl
  • R 2 3 is
  • R 1 2 is independently unsubstituted alkyl; R 1 3 is independently -OR 1D ; R 1 5 is independently -OR 1D ; R 2 3 is independently -OR 2D ; and each R 1D and R 2D is independently hydrogen, -CX 3 , -CHX 2 , -CH 2 X, substituted or unsubstituted alkyl.
  • R 1 2 is independently unsubstituted Ci-Cs alkyl;
  • R 1 3 is independently -OR 1D ;
  • R 1 5 is independently -OR 1D ;
  • R 2 3 is independently -OR 2D ; and each R 1D and R 2D is independently hydrogen or substituted or unsubstituted Ci-Cs alkyl.
  • R 1 2 is independently unsubstituted C1-C5 alkyl; R 1 3 is independently -OH; R 1 5 is independently -OR 1D ; R 2 3 is independently -OH; and R 1D is independently hydrogen or unsubstituted C1-C4 alkyl.
  • R 1 2 is independently unsubstituted C1-C5 alkenyl; R 1 3 is independently -OH; R 1 5 is independently -OR 1D ; R 2 3 is independently -OH; and R 1D is independently unsubstituted C1-C2 alkyl.
  • R 1 2 has the formula ; R 1 3 is independently -OH; R 1 5 is independently -OR 1D ; R 2 3 is
  • R 1D is independently unsubstituted C1-C2 alkyl.
  • R 1 is independently halogen, -CX ⁇ , -CHX ⁇ , -CH2X 1 , -OCXS, - OCH2X 1 , -OCHX 1 !, -CN, -SR 1D , - R 1A R 1B , -C(0)R 1C , -C(0)0R 1C , -C(0) R 1A R 1B , -OR 1D , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 1 is independently halogen, -CX ⁇ , -CHX ⁇ , -CH2X 1 , -OCXS, - OCH2X 1 , -OCHX ⁇ , -CN, -SH, -NH 2 , -C(0)OH, -C(0)NH 2 , -OH, substituted or unsubstituted Ci-C 8 alkyl, or substituted or unsubstituted 2 to 8 membered heteroalkyl; substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted 3 to 8 membered
  • heterocycloalkyl substituted or unsubstituted C 6 -Ci2 aryl, or substituted or unsubstituted 5 to 12 membered heteroaryl.
  • R 1 is independently halogen, -CX ⁇ , -CHX ⁇ , -CH2X 1 , -OCXS, - OCH2X 1 , -OCHX ⁇ , -CN, -SH, -NH 2 , -C(0)OH, -C(0)NH 2 , -OH, substituted or unsubstituted Ci-C 8 alkyl, or substituted or unsubstituted 2 to 8 membered heteroalkyl; substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted 3 to 8 membered
  • heterocycloalkyl substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.
  • two adjacent R 1 substituents are joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • two adjacent R 1 substituents are joined to form an unsubstituted cycloalkyl.
  • two adjacent R 1 substituents are joined to form an unsubstituted C 3 -C 6 cycloalkyl.
  • R 1 is independently -CI. In embodiments, R 1 is independently halogen. In embodiments, R 1 is independently unsubstituted methyl. In embodiments, R 1 is independently unsubstituted ethyl. In embodiments, R 1 is independently unsubstituted propyl. In embodiments, R 1 is independently unsubstituted isopropyl. In embodiments, R 1 is independently unsubstituted n-propyl. In embodiments, R 1 is independently unsubstituted butyl. In embodiments, R 1 is independently unsubstituted n-butyl. In embodiments, R 1 is independently unsubstituted t-butyl.
  • R 1 is independently unsubstituted pentyl. In embodiments, R 1 is independently unsubstituted n-pentyl. In embodiments, R 1 is independently unsubstituted hexyl. In embodiments, R 1 is independently unsubstituted n- hexyl. In embodiments, R 1 is independently unsubstituted heptyl. In embodiments, R 1 is independently unsubstituted n-heptyl. In embodiments, R 1 is independently unsubstituted octyl. In embodiments, R 1 is independently unsubstituted n-octyl. In embodiments, R 1 is independently unsubstituted benzyl.
  • R 1 is independently unsubstituted Ci- C 8 alkyl. In embodiments, R 1 is independently halo-substituted methyl. In embodiments, R 1 is independently halo-substituted ethyl. In embodiments, R 1 is independently halo- substituted isopropyl. In embodiments, R 1 is independently halo- substituted n-propyl. In embodiments, R 1 is independently halo- substituted n-butyl. In embodiments, R 1 is independently halo- substituted t-butyl. In embodiments, R 1 is independently halo-substituted n-pentyl.
  • R 1 is independently halo-substituted benzyl. In embodiments, R 1 is independently halo-substituted Ci-C 8 alkyl. In embodiments, R 1 is independently unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R 1 is independently
  • R 1 is independently
  • R 1 is independently
  • R 1 is independently
  • R 1 is independently unsubstituted 2 to 10 membered heteroalkyl. In embodiments, R 1 is independently unsubstituted 3 to 10 membered heteroalkyl. In embodiments, R 1 is independently unsubstituted 4 to 10 membered heteroalkyl. In embodiments, R 1 is independently unsubstituted 5 to 10 membered heteroalkyl. In embodiments, R 1 is independently unsubstituted 6 to 10 membered heteroalkyl. In embodiments, R 1 is independently unsubstituted 7 to 10 membered heteroalkyl. In embodiments, R 1 is independently unsubstituted 8 to 10 membered heteroalkyl. In embodiments, R 1 is independently unsubstituted 6 to 10 membered heteroalkyl. In embodiments, R 1 is independently unsubstituted 7 to 9 membered heteroalkyl.
  • R 1 is independently -CXV In embodiments, R 1 is independently - CHX In embodiments, R 1 is independently -CH2X 1 . In embodiments, R 1 is
  • R 1 independently -OCXS. In embodiments, R 1 is independently -OCH2X 1 . In embodiments, R 1 is independently -OCHX 1 !. In embodiments, R 1 is independently -CN. In embodiments, R 1 is independently -SO n iR 1D . In embodiments, R 1 is independently -SO v i R 1A R 1B . In embodiments, R 1 is independently - HC(0) R 1A R 1B . In embodiments, R 1 is
  • R 1 is independently -N(0) m i.
  • R 1 is independently - R 1A R 1B .
  • R 1 is independently -C(0)R 1C .
  • R 1 is independently -C(0)-0R 1C .
  • R 1 is independently -C(0) R 1A R 1B .
  • R 1 is
  • R 1 is independently -OR 1D .
  • R 1 is independently -NR 1A S0 2 R 1D .
  • R 1 is independently - R 1A C(0)R 1C .
  • R 1 is independently - R 1A C(0)0R 1C .
  • R 1 is independently - R 1A 0R 1C .
  • R 1 is independently -OH.
  • R 1 is independently -NH 2 .
  • R 1 is independently -COOH.
  • R 1 is independently -CO H 2 .
  • R 1 is independently -N0 2 .
  • R 1 is independently -SH.
  • R 1 is independently halogen.
  • R 1 is independently -F. In embodiments, R 1 is independently -CI. In embodiments, R 1 is independently -Br. In embodiments, R 1 is independently -I. In embodiments, R 1 is independently -CF 3 . In embodiments, R 1 is independently -CHF 2 . In embodiments, R 1 is independently -CH 2 F. In embodiments, R 1 is independently -OCF 3 . In embodiments, R 1 is independently -OCH 2 F. In embodiments, R 1 is independently -OCHF 2 . In embodiments, R 1 is independently -OCH 3 . In embodiments, R 1 is independently - OCH 2 CH 3 . In embodiments, R 1 is independently -OCH 2 CH 2 CH 3 .
  • R 1 is independently -OCH(CH 3 ) 2 . In embodiments, R 1 is independently -OC(CH 3 ) 3 . In embodiments, R 1 is independently -SCH 3 . In embodiments, R 1 is independently -SCH 2 CH 3 . In embodiments, R 1 is independently -SCH 2 CH 2 CH 3 . In embodiments, R 1 is independently - SCH(CH 3 ) 2 . In embodiments, R 1 is independently -SC(CH 3 ) 3 . In embodiments, R 1 is independently -CH 3 . In embodiments, R 1 is independently -CH 2 CH 3 . In embodiments, R 1 is independently -CH 2 CH 2 CH 3 . In embodiments, R 1 is independently -CH(CH 3 ) 2 . In embodiments, R 1 is independently -C(CH 3 ) 3 .
  • R 1 is independently hydrogen, halogen, -CX X 3 , -CHX X 2 , -
  • R 1 is independently substituted or unsubstituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 1 is independently substituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 1 is independently unsubstituted alkyl (e.g., Ci- C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 1 is independently unsubstituted methyl. In embodiments, R 1 is independently unsubstituted ethyl.
  • R 1 is independently unsubstituted propyl. In embodiments, R 1 is independently unsubstituted isopropyl. In embodiments, R 1 is independently unsubstituted tert-butyl. In embodiments, R 1 is independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R 1 is independently substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 1 is independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 1 is independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 1 is independently substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6 ).
  • R 1 is independently substituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6 ).
  • R 1 is independently unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6 ).
  • R 1 is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 1 is independently substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 1 is independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R 1 is independently substituted or unsubstituted aryl (e.g., C6-C12, C 6 -Cio, or phenyl). In embodiments, R 1 is independently substituted aryl (e.g., C 6 -Ci2, C 6 -Cio, or phenyl). In embodiments, R 1 is independently unsubstituted aryl (e.g., C 6 -Ci2, C 6 -Cio, or phenyl).
  • aryl e.g., C 6 -Ci2, C 6 -Cio, or phenyl.
  • R 1 is independently substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R 1 is independently substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R 1 is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • two adjacent R 1 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6).
  • a substituted or unsubstituted cycloalkyl e.g., C3-C8, C3-C6, C4-C6, or C5-C6.
  • two adjacent R 1 substituents may optionally be joined to form a substituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6).
  • two adjacent R 1 substituents may optionally be joined to form an unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6).
  • two adjacent R 1 substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • two adjacent R 1 substituents may optionally be joined to form a substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • two adjacent R 1 substituents may optionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • two adjacent R 1 substituents may optionally be joined to form a substituted or unsubstituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl). In embodiments, two adjacent R 1 substituents may optionally be joined to form a substituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl). In embodiments, two adjacent R 1 substituents may optionally be joined to form an unsubstituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • two adjacent R 1 substituents may optionally be joined to form a substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • two adjacent R 1 substituents may optionally be joined to form a substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • two adjacent R 1 substituents may optionally be joined to form an unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 1A is independently hydrogen. In embodiments, R 1A is independently -CX 1A 3. In embodiments, R 1A is independently -CHX 1A 2 . In embodiments, R 1A is independently -CH 2 X 1A . In embodiments, R 1A is independently -CN. In
  • R 1A is independently -COOH. In embodiments, R 1A is
  • R 1A is independently substituted or unsubstituted alkyl (e.g., Ci- C 8 , Ci-C 6 , C1-C4, or Ci-C 2 ). In embodiments, R 1A is independently substituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or Ci-C 2 ). In embodiments, R 1A is independently unsubstituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or Ci-C 2 ).
  • R 1A is independently unsubstituted methyl. In embodiments, R is independently unsubstituted ethyl. In embodiments, R is independently unsubstituted propyl. In embodiments, R 1A is independently unsubstituted isopropyl. In embodiments, R 1A is independently unsubstituted tert-butyl. In embodiments, R 1A is independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • heteroalkyl e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered.
  • R 1A is independently substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 1A is independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 1A is independently substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6).
  • R 1A is independently substituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R 1A is independently unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R 1A is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 1A is independently substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R 1A is independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R 1A is
  • R 1A independently substituted or unsubstituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • R 1A is independently substituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • R 1A is independently unsubstituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • R 1A is independently substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 1A is independently substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R 1A is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6
  • R 1B is independently hydrogen. In embodiments, R 1B is independently -CX 1B 3. In embodiments, R 1B is independently -CHX 1B 2. In embodiments, R 1B is independently -CH2X 1B . In embodiments, R 1B is independently -CN. In embodiments, R 1B is independently -COOH. In embodiments, R 1B is independently -CO H2. In embodiments, X 1B is independently -F, -CI, -Br, or -I. [0153] In embodiments, R is independently substituted or unsubstituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2).
  • R is independently substituted or unsubstituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2).
  • R 1B is independently substituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 1B is independently unsubstituted alkyl (e.g., Ci- C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 1B is independently unsubstituted methyl. In embodiments, R 1B is independently unsubstituted ethyl. In embodiments, R 1B is
  • R 1B independently unsubstituted propyl.
  • R 1B is independently unsubstituted isopropyl.
  • R 1B is independently unsubstituted tert-butyl.
  • R 1B is independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 1B is independently substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 1B is independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 1B is independently substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6 ).
  • R 1B is independently substituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6 ).
  • R 1B is independently unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6 ).
  • R 1B is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 1B is independently substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 1B is independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R 1B is
  • R 1B is independently substituted or unsubstituted aryl (e.g., C6-C12, C 6 -Cio, or phenyl).
  • R 1B is independently substituted aryl (e.g., C 6 -Ci2, C 6 -Cio, or phenyl).
  • R 1B is independently unsubstituted aryl (e.g., C 6 -Ci2, C 6 -Cio, or phenyl).
  • R 1B is independently substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 1B is independently substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R 1B is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6
  • R 1A and R 1B substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R and R 1B substituents bonded to the same nitrogen atom may be joined to form a substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 1A and R 1B substituents bonded to the same nitrogen atom may be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • an unsubstituted heterocycloalkyl e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered.
  • R 1A and R 1B substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 1A and R 1B may be joined to form a substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 1A and R 1B may be joined to form a substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 1C is independently hydrogen.
  • R 1C is independently -CX 1C 3 .
  • R 1C is independently -CHX 1C 2.
  • R 1C is independently -01 ⁇ 4 ⁇ 1 ⁇ : .
  • R 1C is independently -CN.
  • R 1C is independently -COOH.
  • R 1C is independently -CO H2.
  • X 1C is independently -F, -CI, -Br, or -I.
  • R 1C is independently substituted or unsubstituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2).
  • R 1C is independently substituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2).
  • R 1C is independently unsubstituted alkyl (e.g., Ci- C 8 , Ci-C 6 , C1-C4, or C1-C2).
  • R 1C is independently unsubstituted methyl.
  • R 1C is independently unsubstituted ethyl.
  • R 1C is
  • R 1C independently unsubstituted propyl.
  • R 1C is independently unsubstituted isopropyl.
  • R 1C is independently unsubstituted tert-butyl.
  • R 1C is independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 1C is independently substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 1C is independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 1C is independently substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6).
  • R is independently substituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6).
  • R 1C is independently unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6).
  • R 1C is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 1C is independently substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 1C is independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R 1C is
  • R 1C independently substituted or unsubstituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • R 1C is independently substituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • R 1C is independently unsubstituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • R 1C is independently substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 1C is independently substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R 1C is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6
  • R 1D is independently hydrogen. In embodiments, R 1D is independently -CX 1D 3. In embodiments, R 1D is independently -CHX 1D 2. In embodiments, R 1D is independently -CH 2 X 1D . In embodiments, R 1D is independently -CN. In
  • R 1D is independently -COOH. In embodiments, R 1D is
  • X 1D is independently -F, -CI, -Br, or -I.
  • R 1D is independently substituted or unsubstituted alkyl (e.g., Ci- C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 1D is independently substituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 1D is independently unsubstituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 1D is independently unsubstituted methyl. In embodiments, R 1D is independently unsubstituted ethyl.
  • R 1D is independently unsubstituted propyl. In embodiments, R 1D is independently unsubstituted isopropyl. In embodiments, R 1D is independently unsubstituted tert-butyl. In embodiments, R 1D is independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R 1D is independently substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R is independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 1D is independently substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6).
  • R 1D is independently substituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6).
  • R 1D is independently unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6).
  • R 1D is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 1D is independently substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 1D is independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R 1D is
  • R 1D is independently substituted or unsubstituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • R 1D is independently substituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • R 1D is independently unsubstituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • R 1D is independently substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 1D is independently substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R 1D is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6
  • R 1 is independently hydrogen
  • R 1 is independently hydrogen
  • X 1 is independently - F, -CI, -Br, or -I.
  • R 1 is independently hydrogen.
  • R 1 is independently unsubstituted methyl.
  • R 1 is independently unsubstituted ethyl.
  • two adjacent R 1 substituents may optionally be joined to form a R 20 -substituted or unsubstituted cycloalkyl (e.g., C3-C 8 , C3-C6, C4-G5, or C5-C 6 ).
  • two adjacent R 1 substituents may optionally be joined to form a R 20 -substituted cycloalkyl (e.g., C3-C 8 , C3-C6, C4-C6, or C5-C 6 ).
  • two adjacent R 1 substituents may optionally be joined to form an unsubstituted cycloalkyl (e.g., C3-C 8 , C3-C6, C4-C6, or C5-C 6 ).
  • two adjacent R 1 substituents may optionally be joined to form a R 20 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • two adjacent R 1 substituents may optionally be joined to form a R 20 -substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • two adjacent R 1 substituents may optionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • two adjacent R 1 substituents may optionally be joined to form a R 20 -substituted or unsubstituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • two adjacent R 1 substituents may optionally be joined to form a R 20 -substituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • two adjacent R 1 substituents may optionally be joined to form an unsubstituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • two adjacent R 1 substituents may optionally be joined to form a R 20 -substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • two adjacent R 1 substituents may optionally be joined to form a R 20 -substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • two adjacent R 1 substituents may optionally be joined to form an unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 20 is independently oxo
  • R 20 is independently oxo
  • R 20 is independently unsubstituted ethyl.
  • R 21 is independently oxo
  • R 21 is independently oxo
  • R 21 is independently unsubstituted ethyl.
  • R 22 is independently oxo
  • R 22 is independently unsubstituted ethyl.
  • zl is 0. In embodiments, zl is 1. In embodiments, zl is 2. In embodiments, zl is 3. In embodiments, zl is 4. In embodiments, zl is 5.
  • R 2 is independently halogen, -CX 2 3 , -CHX 2 2 , -CH 2 X 2 , -OCX 2 3 , - OCH2X 2 , -OCHX 2 2, -CN, -SR 2D , - R 2A R 2B , -C(0)R 2C , -C(0)OR 2C , -C(0) R 2A R 2B , -OR 2D , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 2 is independently halogen, -CX 2 3 , -CHX 2 2 , -CH 2 X 2 , -OCX 2 3 , - OCH2X 2 , -OCHX 2 2, -CN, -SH, -NH2, -C(0)OH, -C(0)NH 2 , -OH, substituted or unsubstituted Ci-C 8 alkyl, or substituted or unsubstituted 2 to 8 membered heteroalkyl; substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted 3 to 8 membered
  • heterocycloalkyl substituted or unsubstituted C 6 -Ci 2 aryl, or substituted or unsubstituted 5 to 12 membered heteroaryl.
  • R 2 is independently halogen, -CX 2 3 , -CHX 2 2 , -CH 2 X 2 , -OCX 2 3 , - OCH2X 2 , -OCHX 2 2, -CN, -SH, -NH 2 , -C(0)OH, -C(0)NH 2 , -OH, substituted or unsubstituted Ci-C 8 alkyl, or substituted or unsubstituted 2 to 8 membered heteroalkyl; substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted 3 to 8 membered
  • heterocycloalkyl substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.
  • two adjacent R 2 substituents are joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • two adjacent R 2 substituents are joined to form an unsubstituted cycloalkyl.
  • two adjacent R 2 substituents are joined to form an unsubstituted C 3 -C 6 cycloalkyl.
  • R 2 is independently -CX 2 3 .
  • R 2 is independently - CHX 2 2.
  • R 2 is independently -CH2X 2 .
  • R 2 is
  • R 2 independently -OCX 2 3 .
  • R 2 is independently -OCH2X 2 .
  • R 2 is independently -OCHX 2 2.
  • R 2 is independently -CN.
  • R 2 is independently -SC R 20
  • R 2 is independently -SO V 2 R 2A R 2B .
  • R 2 is independently - HC(0) R 2A R 2B .
  • R 2 is independently - HC(0) R 2A R 2B .
  • R 2 is independently -N(0) m 2.
  • R 2 is independently - R 2A R 2B .
  • R 2 is independently -C(0)R 2C .
  • R 2 is independently -C(0)-OR 2C .
  • R 2 is independently -C(0) R 2A R 2B .
  • R 2 is
  • R 2 is independently -OR 2D .
  • R 2 is independently -NR 2A S0 2 R 2D .
  • R 2 is independently - R 2A C(0)R 2C .
  • R 2 is independently - R 2A C(0)OR 2C .
  • R 2 is independently - R 2A OR 2C .
  • R 2 is independently -OH.
  • R 2 is independently -NH2.
  • R 2 is independently -COOH.
  • R 2 is independently -CO H2.
  • R 2 is independently -NO2.
  • R 2 is independently -SH.
  • R 2 is independently halogen.
  • R 2 is independently -F.
  • R 2 is independently -CI. In embodiments, R 2 is independently -Br. In embodiments, R 2 is independently -I. In embodiments, R 2 is independently -CF 3 . In embodiments, R 2 is independently -CHF2. In embodiments, R 2 is independently -CH2F. In embodiments, R 2 is independently -OCF 3 . In embodiments, R 2 is independently -OCH2F. In embodiments, R 2 is independently -OCHF2. In embodiments, R 2 is independently -OCH 3 . In embodiments, R 2 is independently - OCH2CH 3 . In embodiments, R 2 is independently -OCH2CH2CH3. In embodiments, R 2 is independently -OCH(CH 3 )2.
  • R 2 is independently -OC(CH 3 ) 3 . In embodiments, R 2 is independently -SCH 3 . In embodiments, R 2 is independently -SCH2CH 3 . In embodiments, R 2 is independently -SCH2CH2CH 3 . In embodiments, R 2 is independently - SCH(CH 3 )2. In embodiments, R 2 is independently -SC(CH 3 ) 3 . In embodiments, R 2 is independently -CH 3 . In embodiments, R 2 is independently -CH2CH 3 . In embodiments, R 2 is independently -CH2CH2CH 3 . In embodiments, R 2 is independently -CH(CH 3 )2. In embodiments, R 2 is independently -C(CH 3 ) 3 . [0172] In embodiments, R 2 is independently hydrogen, halogen, -CX 2 3 , -CHX 2 2, - CH 2 X 2 , -OCX 2 3 , -
  • R 2 is independently substituted or unsubstituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 2 is independently substituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 2 is independently unsubstituted alkyl (e.g., Ci- C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 2 is independently unsubstituted methyl. In embodiments, R 2 is independently unsubstituted ethyl.
  • R 2 is independently unsubstituted propyl. In embodiments, R 2 is independently unsubstituted isopropyl. In embodiments, R 2 is independently unsubstituted tert-butyl. In embodiments, R 2 is independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R 2 is independently substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 2 is independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 2 is independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 2 is independently substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6 ).
  • R 2 is independently substituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6 ).
  • R 2 is independently unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6 ).
  • R 2 is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 2 is independently substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 2 is independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R 2 is independently substituted or unsubstituted aryl (e.g., C 6 -Ci2, C 6 -Cio, or phenyl). In embodiments, R 2 is independently substituted aryl (e.g., C 6 -Ci2, C 6 -Cio, or phenyl).
  • R 2 is independently unsubstituted aryl (e.g., C 6 -Ci2, C 6 -Cio, or phenyl).
  • R 2 is independently substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 2 is independently substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 2 is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • two adjacent R 2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6).
  • a substituted or unsubstituted cycloalkyl e.g., C3-C8, C3-C6, C4-C6, or C5-C6.
  • two adjacent R 2 substituents may optionally be joined to form a substituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6).
  • two adjacent R 2 substituents may optionally be joined to form an unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6).
  • two adjacent R 2 substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • two adjacent R 2 substituents may optionally be joined to form a substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • two adjacent R 2 substituents may optionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • two adjacent R 2 substituents may optionally be joined to form a substituted or unsubstituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl). In embodiments, two adjacent R 2 substituents may optionally be joined to form a substituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl). In embodiments, two adjacent R 2 substituents may optionally be joined to form an unsubstituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • two adjacent R 2 substituents may optionally be joined to form a substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • two adjacent R 2 substituents may optionally be joined to form a substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • two adjacent R 2 substituents may optionally be joined to form an unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 2A is independently hydrogen. In embodiments, R 2A is independently -CX 2A 3. In embodiments, R 2A is independently -CHX 2A 2 . In embodiments, R 2A is independently -CH 2 X 2A . In embodiments, R 2A is independently -CN. In embodiments, R is independently -COOH. In embodiments, R is
  • X 2A is independently -F, -CI, -Br, or -I.
  • R 2A is independently substituted or unsubstituted alkyl (e.g., Ci- C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 2A is independently substituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 2A is independently unsubstituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 2A is independently unsubstituted methyl. In embodiments, R 2A is independently unsubstituted ethyl.
  • R 2A is independently unsubstituted propyl. In embodiments, R 2A is independently unsubstituted isopropyl. In embodiments, R 2A is independently unsubstituted tert-butyl. In embodiments, R 2A is independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R 2A is independently substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 2A is independently substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 2A is independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 2A is independently substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-G5, or C5-C 6 ).
  • R 2A is independently substituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6 ).
  • R 2A is independently unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6 ).
  • R 2A is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 2A is independently substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 2A is independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R 2A is
  • R 2A independently substituted or unsubstituted aryl (e.g., C6-C12, C 6 -Cio, or phenyl).
  • R 2A is independently substituted aryl (e.g., C 6 -Ci2, C 6 -Cio, or phenyl).
  • R 2A is independently unsubstituted aryl (e.g., C 6 -Ci2, C 6 -Cio, or phenyl).
  • R 2A is independently substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 2A is independently substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R 2A is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6
  • R is independently hydrogen. In embodiments, R is independently -CX 2B 3 . In embodiments, R 2B is independently -CHX 2B 2. In embodiments, R 2B is independently -CH2X 2B . In embodiments, R 2B is independently -CN. In embodiments, R 2B is independently -COOH. In embodiments, R 2B is independently -CO H2. In embodiments, R is independently hydrogen. In embodiments, R is independently -CX 2B 3 . In embodiments, R 2B is independently -CHX 2B 2. In embodiments, R 2B is independently -CH2X 2B . In embodiments, R 2B is independently -CN. In embodiments, R 2B is independently -COOH. In embodiments, R 2B is independently -CO H2. In
  • X 2B is independently -F, -CI, -Br, or -I.
  • R 2B is independently substituted or unsubstituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 2B is independently substituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 2B is independently unsubstituted alkyl (e.g., Ci- C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 2B is independently unsubstituted methyl. In embodiments, R 2B is independently unsubstituted ethyl. In embodiments, R 2B is
  • R 2B is independently unsubstituted propyl.
  • R 2B is independently unsubstituted isopropyl.
  • R 2B is independently unsubstituted tert-butyl.
  • R 2B is independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 2B is independently substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 2B is independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 2B is independently substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-G5, or C5-C 6 ).
  • R 2B is independently substituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6 ).
  • R 2B is independently unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-G5).
  • R 2B is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 2B is independently substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 2B is independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R 2B is
  • R 2B is independently substituted or unsubstituted aryl (e.g., C6-C12, C 6 -Cio, or phenyl).
  • R 2B is independently substituted aryl (e.g., C 6 -Ci2, C 6 -Cio, or phenyl).
  • R 2B is independently unsubstituted aryl (e.g., C 6 -Ci2, C 6 -Cio, or phenyl).
  • R 2B is independently substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 2B is independently substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6
  • R 2A and R 2B substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 2A and R 2B substituents bonded to the same nitrogen atom may be joined to form a substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 2A and R 2B substituents bonded to the same nitrogen atom may be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • an unsubstituted heterocycloalkyl e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered.
  • R 2A and R 2B substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 2A and R 2B may be joined to form a substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 2C is independently hydrogen.
  • R 2C is independently -CX 2C 3 .
  • R 2C is independently -CHX 2C 2.
  • R 2C is independently -CIHhX 20 .
  • R 2C is independently -CN.
  • R 2C is independently -COOH.
  • R 2C is independently -CO H2.
  • X 2C is independently -F, -CI, -Br, or -I.
  • R 2C is independently substituted or unsubstituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2).
  • R 2C is independently substituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2).
  • R 2C is independently unsubstituted alkyl (e.g., Ci- C 8 , Ci-C 6 , C1-C4, or C1-C2).
  • R 2C is independently unsubstituted methyl.
  • R 2C is independently unsubstituted ethyl.
  • R 2C is
  • R 2C is independently unsubstituted propyl.
  • R 2C is independently unsubstituted isopropyl.
  • R 2C is independently unsubstituted tert-butyl.
  • R 2C is independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R is independently substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 2C is independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 2C is independently substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6).
  • R 2C is independently substituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6).
  • R 2C is independently unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6).
  • R 2C is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 2C is independently substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 2C is independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R 2C is
  • R 2C is independently substituted or unsubstituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • R 2C is independently substituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • R 2C is independently unsubstituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • R 2C is independently substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 2C is independently substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R 2C is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6
  • R 2D is independently hydrogen. In embodiments, R 2D is independently -CX 2D 3. In embodiments, R 2D is independently -CHX 2D 2. In embodiments, R 2D is independently -CH 2 X 2D . In embodiments, R 2D is independently -CN. In
  • R 2D is independently -COOH. In embodiments, R 2D is
  • X 2D is independently -F, -CI, -Br, or -I.
  • R 2D is independently substituted or unsubstituted alkyl (e.g., Ci- C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 2D is independently substituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 2D is independently unsubstituted alkyl (e.g., Ci-C 8 , Ci-C 6 , C1-C4, or C1-C2). In embodiments, R 2D is independently unsubstituted methyl. In embodiments, R 2D is independently unsubstituted ethyl.
  • R 2D is independently unsubstituted propyl. In embodiments, R is independently unsubstituted isopropyl. In embodiments, R 2D is independently unsubstituted tert-butyl. In embodiments, R 2D is independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R 2D is independently substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 2D is independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 2D is independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).
  • R 2D is independently substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6).
  • R 2D is independently substituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6).
  • R 2D is independently unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6).
  • R 2D is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 2D is independently substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • R 2D is independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R 2D is
  • R 2D is independently substituted or unsubstituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • R 2D is independently substituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • R 2D is independently unsubstituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • R 2D is independently substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 2D is independently substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R 2D is independently unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6
  • R 2 is independently hydrogen
  • R 2 is independently
  • R 2 is independently hydrogen
  • X 2 is independently - F, -CI, -Br, or -I.
  • R 2 is independently hydrogen.
  • R 2 is independently unsubstituted methyl.
  • R 2 is independently unsubstituted ethyl.
  • two adjacent R 2 substituents may optionally be joined to form a R 23 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-G5, or C5-C 6 ).
  • two adjacent R 2 substituents may optionally be joined to form a R 23 -substituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4-C6, or C5-C 6 ).
  • two adjacent R 2 substituents may optionally be joined to form an unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6).
  • two adjacent R 2 substituents may optionally be joined to form a R 23 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • two adjacent R 2 substituents may optionally be joined to form a R 23 -substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • two adjacent R 2 substituents may optionally be joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • two adjacent R 2 substituents may optionally be joined to form a R 23 -substituted or unsubstituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • two adjacent R 2 substituents may optionally be joined to form a R 23 -substituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • two adjacent R 2 substituents may optionally be joined to form an unsubstituted aryl (e.g., C 6 -C 12 , C 6 -Cio, or phenyl).
  • two adjacent R 2 substituents may optionally be joined to form a R 23 -substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • two adjacent R 2 substituents may optionally be joined to form a R 23 -substituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • two adjacent R 2 substituents may optionally be joined to form an unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
  • R 23 is independently oxo
  • R 23 is independently oxo
  • R 23 is independently unsubstituted ethyl.
  • R 24 is independently oxo
  • R 24 is independently oxo
  • R 24 is independently unsubstituted ethyl. [0190] R is independently oxo,
  • R 25 is independently unsubstituted ethyl.
  • z2 is 0. In embodiments, z2 is 1. In embodiments, z2 is 2. In embodiments, z2 is 3. In embodiments, z2 is 4. [0192] In embodiments, X is -F. In embodiments, X is -CI. In embodiments, X is -Br. In embodiments, X is -I. In embodiments, X 1 is -F. In embodiments, X 1 is -CI. In
  • X 1 is -Br. In embodiments, X 1 is -I. In embodiments, X 2 is -F. In
  • X 2 is -CI. In embodiments, X 2 is -Br. In embodiments, X 2 is -I.
  • nl is 0. In embodiments, nl is 1. In embodiments, nl is 2. In embodiments, nl is 3. In embodiments, nl is 4. In embodiments, n2 is 0. In embodiments, n2 is 1. In embodiments, n2 is 2. In embodiments, n2 is 3. In embodiments, n2 is 4.
  • ml is 1. In embodiments, ml is 2. In embodiments, m2 is 1. In embodiments, m2 is 2.
  • vl is 1. In embodiments, vl is 2. In embodiments, v2 is 1. In embodiments, v2 is 2.
  • a compound as described herein may include multiple instances of R 1 or R 2 , and/or other variables.
  • each variable may optional be different and be appropriately labeled to distinguish each group for greater clarity.
  • R 1 and/or R 2 may be referred to, for example, as R u , R 1 2 , R 1 3 , R 1 4 , R 1 5 , R 2 R 2 2 , R 2 3 , or R 2 4 , respectively, wherein the definition of R 1 is assumed by R u , R 1 2 , R 1 3 , R 1 4 , R 1 5 ; and/or R 2 is assumed by R 2 ⁇ R 2 2 , R 2 3 , R 2 4 .
  • the compound is a compound described herein (e.g., in an aspect, embodiment, example, claim, table, scheme, drawing, or figure). [0197] In embodiments, unless otherwise indicated, a compound described herein is a racemic mixture of all stereoisomers. In embodiments, unless otherwise indicated, a compound described herein is a racemic mixture of all enantiomers. In embodiments, unless otherwise indicated, a compound described herein is a racemic mixture of two opposite stereoisomers.
  • a compound described herein is a racemic mixture of two opposite enantiomers. In embodiments, unless otherwise indicated, a compound described herein is a single stereoisomer. In embodiments, unless otherwise indicated, a compound described herein is a single enantiomer. In embodiments, the compound is a compound described herein (e.g., in an aspect, embodiment, example, figure, table, scheme, or claim). [0198] In an aspect is provided a PTGR1 inhibitor. In embodiments, the PTGR1 inhibitor is a compound described herein.
  • the PTGR1 inhibitor is an oligonucleotide (e.g., DNA, RNA, shRNA, or siRNA), protein (e.g., antibody, anti-PTGRl antibody, anti- PTGR1 binding antibody fragment), or compound (e.g., compound described herein).
  • the PTGR1 inhibitor contacts one or more amino acids corresponding to P48, M124, T128, A149, A153, V154, N217, C239, Y245, V271, or V272 of human PTGR1.
  • the PTGR1 inhibitor contacts one or more amino acids corresponding to P48, M124, T128, A149, A153, V154, N217, Y245, V271, or V272 of human PTGR1. In embodiments, the PTGR1 inhibitor contacts one or more amino acids corresponding to P48, M124, T128, A149, A153, N217, C239, Y245, V271, or V272 of human PTGR1. In embodiments, the PTGR1 inhibitor contacts one or more amino acids corresponding to P48, M124, T128, A149, A153, N217, Y245, V271, or V272 of human PTGR1.
  • the PTGR1 inhibitor covalently binds an amino acid corresponding to C239 in human PTGR1. In embodiments, the PTGR1 inhibitor contacts an amino acid corresponding to C239 in human PTGR1. In embodiments, the PTGR1 inhibitor contacts an amino acid corresponding to P48 in human PTGR1. In embodiments, the PTGR1 inhibitor contacts an amino acid corresponding to M124 in human PTGR1. In embodiments, the PTGR1 inhibitor contacts an amino acid corresponding to T128 in human PTGR1. In embodiments, the PTGR1 inhibitor contacts an amino acid corresponding to A149 in human PTGR1. In embodiments, the PTGRl inhibitor contacts an amino acid corresponding to A153 in human PTGRl .
  • the PTGRl inhibitor contacts an amino acid corresponding to VI 54 in human PTGRl . In embodiments, the PTGRl inhibitor contacts an amino acid corresponding to N217 in human PTGRl . In embodiments, the PTGRl inhibitor contacts an amino acid corresponding to Y245 in human PTGRl . In embodiments, the PTGRl inhibitor contacts an amino acid corresponding to V271 in human PTGRl . In embodiments, the PTGRl inhibitor contacts an amino acid corresponding to V272 in human PTGRl . In embodiments, the PTGRl inhibitor includes an electrophilic group (e.g., electrophilic chemical group, electrophilic moiety, divalent electrophilic group, covalent cysteine modifier).
  • electrophilic group e.g., electrophilic chemical group, electrophilic moiety, divalent electrophilic group, covalent cysteine modifier.
  • a PTGRl inhibitor In an aspect is provided a PTGRl inhibitor.
  • the PTGRl inhibitor is a compound described herein.
  • the PTGRl inhibitor is an oligonucleotide (e.g., DNA, RNA, shRNA, or siRNA), antisense nucleic acid, protein (e.g., antibody, anti- PTGR1 antibody, anti-PTGRl binding antibody fragment), or compound (e.g., compound described herein).
  • the PTGRl inhibitor contacts one or more amino acids corresponding to P48, M124, T128, A149, A153, V154, N217, C239, Y245, V271, or V272 of SEQ ID NO: 1.
  • the PTGRl inhibitor covalently binds an amino acid corresponding to C239 in SEQ ID NO: 1. In embodiments, the PTGRl inhibitor contacts an amino acid corresponding to C239 in SEQ ID NO: 1. In embodiments, the PTGRl inhibitor contacts an amino acid corresponding to P48 in SEQ ID NO: 1. In embodiments, the PTGRl inhibitor contacts an amino acid corresponding to M124 in SEQ ID NO: 1. In embodiments, the PTGRl inhibitor contacts an amino acid corresponding to T 128 in SEQ ID NO: 1. In embodiments, the PTGRl inhibitor contacts an amino acid corresponding to A149 in SEQ ID NO: l . In embodiments, the PTGRl inhibitor contacts an amino acid corresponding to A153 in SEQ ID NO: 1. In embodiments, the PTGRl inhibitor contacts an amino acid
  • the PTGRl inhibitor contacts an amino acid corresponding to N217 in SEQ ID NO: 1. In embodiments, the PTGRl inhibitor contacts an amino acid corresponding to Y245 in SEQ ID NO: 1. In embodiments, the PTGRl inhibitor contacts an amino acid corresponding to V271 in SEQ ID NO: 1. In embodiments, the PTGRl inhibitor contacts an amino acid corresponding to V272 in SEQ ID NO: l . In embodiments, the PTGRl inhibitor includes an electrophilic group (e.g., electrophilic chemical group, electrophilic moiety, divalent electrophilic group, covalent cysteine modifier). [0200] In embodiments, the compound is a compound described herein, including in an aspect, embodiment, claim, figure, table, example, or scheme.
  • the compound has the formula:
  • the compound has the formula: [0207] In embodiments, the compound has the formula:
  • the compound has the formula:
  • the compound has the formula:
  • the compound has the formula:
  • the compound has the formula: [0212] In embodiments, the compound has the formula:
  • the compound has the formula:
  • the compound has the formula:
  • the compound is licochalcone A, having the formula:
  • the compound is not licochalcone
  • the compound is a derivative of licochalcone A. In embodiments, the compound is an analog of licochalcone A. In embodiments, the compound is a prodrug (e.g., physiologically hydrolyzable ester thereof) of licochalcone A. In embodiments, the compound is not 2-hydroxychalcone. In embodiments, the compound is not xanthohumol. In embodiments, the compound is not an analog, derivative, or prodrug of 2-hydroxychalcone. In embodiments, the compound is not an analog, derivative, or prodrug of xanthohumol. III. Pharmaceutical compositions
  • a pharmaceutical composition including a PTGRl inhibitor and a pharmaceutically acceptable excipient.
  • the PTGRl inhibitor is a compound described herein.
  • the PTGRl inhibitor is an oligonucleotide (e.g., DNA, RNA, or siRNA), protein (e.g., antibody, anti-PTGRl antibody, anti-PTGRl binding antibody fragment), or compound (e.g., compound described herein).
  • the PTGRl inhibitor is included in a therapeutically effective amount.
  • the pharmaceutical composition does not include licochalcone A.
  • composition including a compound described herein, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • pharmaceutically acceptable salt thereof is included in a therapeutically effective amount.
  • composition includes a second agent (e.g. therapeutic agent).
  • the pharmaceutical composition includes a second agent (e.g. therapeutic agent) in a therapeutically effective amount.
  • the second agent is an agent for treating cancer.
  • the second agent is an anti-cancer agent. In embodiments, the second agent is a chemotherapeutic.
  • a method of treating cancer including administering to a subject in need thereof an effective amount of a PTGRl inhibitor.
  • the PTGRl inhibitor is a compound described herein.
  • the PTGRl inhibitor is an oligonucleotide (e.g., DNA, RNA, or siRNA), antisense nucleic acid, protein (e.g., antibody, anti-PTGRl antibody, anti-PTGRl binding antibody fragment), or compound (e.g., compound described herein).
  • the PTGRl inhibitor is included in a therapeutically effective amount.
  • a method of treating triple negative breast cancer including administering to a subject in need thereof an effective amount of a PTGRl inhibitor.
  • the PTGRl inhibitor is a compound described herein.
  • the PTGRl inhibitor is an oligonucleotide (e.g., DNA, RNA, or siRNA), antisense nucleic acid, protein (e.g., antibody, anti-PTGRl antibody, anti-PTGRl binding antibody fragment), or compound (e.g., compound described herein).
  • the PTGRl inhibitor is included in a therapeutically effective amount.
  • the PTGRl inhibitor is a chalcone or chalconoid (e.g., 1,3- diphenyl-2-propenone, butein, isoliquiritigenin, methyl hydroxychalcone, okanin, licochalcone a, sophoradin, tephrospinosin (3',5'-diisopentenyl-2',4'-dihydroxychalcone), xanthohumol, cardamomin, flavokawin b, okanin ((E)-3-(3,4-dihydroxyphenyl)-l-(2,3,4- trihydroxyphenyl)prop-2-en-l-one), methylated okanin derivatives (e.g., okanin 3,4,3 ',4'- tetramethyl ether, okanin 3,4,3 '-trimethyl ether 4'-glucoside, okanin 4-methyl ether 4'- glucoside and
  • the PTGRl inhibitor has the following formula:
  • the cancer is lung cancer.
  • the cancer is prostate cancer.
  • the cancer is breast cancer.
  • the cancer is estrogen receptor positive breast cancer.
  • the cancer is estrogen receptor (ER) negative breast cancer.
  • the cancer is tamoxifen resistant breast cancer.
  • the cancer is HER2 negative breast cancer.
  • the cancer is HER2 positive breast cancer.
  • the cancer is low grade (well differentiated) breast cancer. In embodiments, the cancer is intermediate grade (moderately differentiated) breast cancer.
  • the cancer is high grade (poorly differentiated) breast cancer. In embodiments, the cancer is stage 0 breast cancer. In embodiments, the cancer is stage I breast cancer. In embodiments, the cancer is stage II breast cancer. In embodiments, the cancer is stage III breast cancer. In embodiments, the cancer is stage IV breast cancer. In embodiments, the cancer is triple negative breast cancer.
  • a method of treating a disease associated with PTGRl activity including administering to a subject in need thereof an effective amount of a PTGRl inhibitor.
  • the PTGRl inhibitor is a compound described herein.
  • the PTGRl inhibitor is an oligonucleotide (e.g., DNA, RNA, or siRNA), antisense nucleic acid, protein (e.g., antibody, anti-PTGRl antibody, anti-PTGRl binding antibody fragment), or compound (e.g., compound described herein).
  • the disease is associated with aberrant PTGRl activity.
  • the method includes administering a second agent (e.g. therapeutic agent).
  • the method includes administering a second agent (e.g. therapeutic agent) in a therapeutically effective amount.
  • the second agent is an agent for treating cancer.
  • the second agent is an anti-cancer agent.
  • the second agent is a chemotherapeutic.
  • a method of treating cancer including administering to a subject in need thereof an effective amount of a substance (e.g., composition) capable of increasing the level of an acyl carnitine (AC) (e.g., compared to a control such as absence of the composition).
  • a substance e.g., composition
  • AC acyl carnitine
  • the composition capable of increasing the level of an acyl carnitine is a compound described herein.
  • the composition capable of increasing the level of an acyl carnitine is an oligonucleotide (e.g., DNA, RNA, or siRNA), antisense nucleic acid, protein (e.g., antibody), or compound (e.g., compound described herein).
  • the composition capable of increasing the level of an acyl carnitine is included in a therapeutically effective amount.
  • the composition capable of increasing the level of an acyl carnitine is a deubiquitinase inhibitor (e.g., deubiquitinase inhibitor described herein, WP1130, ESI09, GW4604).
  • the acyl carnitine is described herein, for example in FIGS.
  • the acyl carnitine is C16:0 AC.
  • the method includes reducing mitochondrial respiration.
  • the cancer is breast cancer (e.g., triple negative breast cancer).
  • the method increases the level of activity of carnitine palmitoyltransferase 1 (CPT1) (e.g, compared to a control such as absence of the inhibitor).
  • CPT1 carnitine palmitoyltransferase 1
  • a method of inhibiting PTGRl activity including contacting the PTGRl with a PTGRl inhibitor.
  • the PTGRl is a human PTGRl .
  • the PTGRl inhibitor is a compound described herein.
  • the PTGRl inhibitor is an oligonucleotide (e.g., DNA, RNA, or siRNA), protein (e.g., antibody, anti-PTGRl antibody, anti-PTGRl binding antibody fragment), or compound (e.g., compound described herein).
  • the PTGRl inhibitor is provided in a therapeutically effective amount.
  • the PTGRl inhibitor contacts one or more amino acids corresponding to P48, M124, T128, A149, A153, V154, N217, C239, Y245, V271, or V272 of human PTGRl . In embodiments, the PTGRl inhibitor contacts one or more amino acids corresponding to P48, M124, T128, A149, A153, V154, N217, Y245, V271, or V272 of human PTGRl . In embodiments, the PTGRl inhibitor contacts one or more amino acids corresponding to P48, M124, T128, A149, A153, N217, C239, Y245, V271, or V272 of human PTGRl .
  • the PTGRl inhibitor contacts one or more amino acids corresponding to P48, M124, T128, A149, A153, N217, Y245, V271, or V272 of human PTGRl .
  • the PTGRl inhibitor covalently binds an amino acid corresponding to C239 in human PTGRl .
  • the PTGRl inhibitor contacts an amino acid corresponding to C239 in human PTGRl .
  • the PTGRl inhibitor contacts an amino acid corresponding to P48 in human PTGRl .
  • the PTGRl inhibitor contacts an amino acid corresponding to M124 in human PTGRl .
  • the PTGRl inhibitor contacts an amino acid corresponding to T128 in human PTGRl . In embodiments, the PTGRl inhibitor contacts an amino acid corresponding to A149 in human PTGRl . In embodiments, the PTGRl inhibitor contacts an amino acid corresponding to A153 in human PTGRl . In embodiments, the PTGRl inhibitor contacts an amino acid corresponding to VI 54 in human PTGRl . In embodiments, the PTGRl inhibitor contacts an amino acid corresponding to N217 in human PTGRl . In embodiments, the PTGRl inhibitor contacts an amino acid corresponding to Y245 in human PTGRl . In embodiments, the PTGRl inhibitor contacts an amino acid corresponding to V271 in human PTGRl . In embodiments, the PTGRl inhibitor contacts an amino acid corresponding to V272 in human PTGRl .
  • a method of inhibiting PTGRl activity including contacting the PTGRl with a compound described herein.
  • the PTGRl is a human PTGRl .
  • the compound is provided in an effective amount. In embodiments, the compound is provided in a therapeutically effective amount.
  • the method includes contacting the PTGRl protein with an effective amount of a compound described herein.
  • the compound contacts one or more amino acids corresponding to P48, M124, T128, A149, A153, V154, N217, C239, Y245, V271, or V272 of human PTGRl .
  • the compound contacts one or more amino acids corresponding to P48, M124, T128, A149, A153, V154, N217, Y245, V271, or V272 of human PTGRl .
  • the compound contacts one or more amino acids corresponding to P48, M124, T128, A149, A153, N217, C239, Y245, V271, or V272 of human PTGRl . In embodiments, the compound contacts one or more amino acids corresponding to P48, M124, T128, A149, A153, N217, Y245, V271, or V272 of human PTGRl . In embodiments, the compound covalently binds an amino acid corresponding to C239 in human PTGRl . In embodiments, the compound contacts an amino acid
  • the compound contacts an amino acid corresponding to P48 in human PTGRl . In embodiments, the compound contacts an amino acid corresponding to M124 in human PTGRl . In embodiments, the compound contacts an amino acid corresponding to T128 in human PTGRl . In embodiments, the compound contacts an amino acid corresponding to A149 in human PTGRl .
  • the compound contacts an amino acid corresponding to A153 in human PTGRl . In embodiments, the compound contacts an amino acid corresponding to VI 54 in human PTGRl . In embodiments, the compound contacts an amino acid corresponding to N217 in human PTGRl . In embodiments, the compound contacts an amino acid
  • a method of inhibiting PTGRl activity including contacting the PTGRl with a PTGRl inhibitor.
  • the PTGRl is a SEQ ID NO: 1.
  • the PTGRl inhibitor is a compound described herein.
  • the PTGRl inhibitor is an oligonucleotide (e.g., DNA, RNA, or siRNA), antisense nucleic acid, protein (e.g., antibody, anti-PTGRl antibody, anti-PTGRl binding antibody fragment), or compound (e.g., compound described herein).
  • the PTGRl inhibitor is provided in a therapeutically effective amount.
  • the PTGRl inhibitor contacts one or more amino acids corresponding to P48, M124, T128, A149, A153, V154, N217, C239, Y245, V271, or V272 of SEQ ID NO: 1.
  • the PTGRl inhibitor contacts one or more amino acids corresponding to P48, M124, T128, A149, A153, V154, N217, Y245, V271, or V272 of SEQ ID NO: 1. In embodiments, the PTGRl inhibitor contacts one or more amino acids corresponding to P48, M124, T128, A149, A153, N217, C239, Y245, V271, or V272 of SEQ ID NO: 1. In embodiments, the PTGRl inhibitor contacts one or more amino acids corresponding to P48, M124, T128, A149, A153, N217, Y245, V271, or V272 of SEQ ID NO: 1.
  • the PTGRl inhibitor covalently binds an amino acid corresponding to C239 in SEQ ID NO: 1. In embodiments, the PTGRl inhibitor contacts an amino acid corresponding to C239 in SEQ ID NO: 1. In embodiments, the PTGRl inhibitor contacts an amino acid corresponding to P48 in SEQ ID NO: 1. In embodiments, the PTGRl inhibitor contacts an amino acid corresponding to M124 in SEQ ID NO: 1. In embodiments, the PTGRl inhibitor contacts an amino acid corresponding to T128 in SEQ ID NO: l . In embodiments, the PTGRl inhibitor contacts an amino acid
  • the PTGRl inhibitor contacts an amino acid corresponding to A149 in SEQ ID NO: 1.
  • the PTGRl inhibitor contacts an amino acid corresponding to A153 in SEQ ID NO: l .
  • the PTGRl inhibitor contacts an amino acid corresponding to VI 54 in SEQ ID NO: 1.
  • the PTGRl inhibitor contacts an amino acid corresponding to N217 in SEQ ID NO: 1.
  • the PTGRl inhibitor contacts an amino acid corresponding to Y245 in SEQ ID NO: 1.
  • the PTGRl inhibitor contacts an amino acid corresponding to V271 in SEQ ID NO: l .
  • the PTGRl inhibitor contacts an amino acid
  • a method of inhibiting PTGRl activity including contacting the PTGRl with a compound described herein.
  • the PTGRl is a SEQ ID NO: l .
  • the compound is provided in an effective amount.
  • the compound is provided in a therapeutically effective amount.
  • the method includes contacting the PTGRl protein with an effective amount of a compound described herein.
  • the compound contacts one or more amino acids corresponding to P48, M124, T128, A149, A153, V154, N217, C239, Y245, V271, or V272 of SEQ ID NO: l .
  • the compound contacts one or more amino acids corresponding to P48, M124, T128, A149, A153, V154, N217, Y245, V271, or V272 of SEQ ID NO: l . In embodiments, the compound contacts one or more amino acids corresponding to P48, M124, T128, A149, A153, N217, C239, Y245, V271, or V272 of SEQ ID NO: l . In embodiments, the compound contacts one or more amino acids corresponding to P48, M124, T128, A149, A153, N217, Y245, V271, or V272 of SEQ ID NO: l .
  • the compound covalently binds an amino acid corresponding to C239 in SEQ ID NO: 1. In embodiments, the compound contacts an amino acid corresponding to C239 in SEQ ID NO: 1. In embodiments, the compound contacts an amino acid corresponding to P48 in SEQ ID NO: l . In embodiments, the compound contacts an amino acid corresponding to Ml 24 in SEQ ID NO: 1. In embodiments, the compound contacts an amino acid corresponding to T 128 in SEQ ID NO: 1. In embodiments, the compound contacts an amino acid corresponding to A149 in SEQ ID NO: 1. In embodiments, the compound contacts an amino acid corresponding to A153 in SEQ ID NO: l . In embodiments, the compound contacts an amino acid
  • the compound contacts an amino acid corresponding to N217 in SEQ ID NO: 1. In embodiments, the compound contacts an amino acid corresponding to Y245 in SEQ ID NO: 1. In embodiments, the compound contacts an amino acid corresponding to V271 in SEQ ID NO: 1. In embodiments, the compound contacts an amino acid corresponding to V272 in SEQ ID NO: 1.
  • the inhibition is competitive inhibition. In embodiments, the inhibition is irreversible. In embodiments, the inhibition is reversible. In embodiments, the compound covalently binds to the PTGRl protein (e.g., the covalent bond forming via a reaction involving the electrophilic group and a cysteine (e.g., C239 of SEQ ID NO: 1).
  • the PTGRl protein e.g., the covalent bond forming via a reaction involving the electrophilic group and a cysteine (e.g., C239 of SEQ ID NO: 1).
  • a PTGRl protein e.g., human PTGRl
  • a PTGRl inhibitor covalently bonded to a PTGRl inhibitor
  • the resulting covalent bond is reversible.
  • the bonding reverses upon denaturation of the protein.
  • the reversibility of a covalent bond between the compound and the PTGRl upon denaturation of the PTGRl avoids or decreases autoimmune response in a subject subsequent to administration of the compound (relative to irreversibility).
  • the reversibility of a covalent bond between the compound and the PTGRl upon denaturation of the PTGRl avoids or decreases the toxicity (e.g. liver toxicity) of the compound in a subject (relative to irreversibility).
  • the PTGRl activity is reducing (e.g., reducing the levels of or reducing the activity of) 15-keto-prostaglandin or leukotriene B4 relative to a control. In embodiments, the PTGRl activity is reducing the level of 15-keto-prostaglandin. In embodiments, the PTGRl activity is reducing the level of leukotriene B4. In embodiments, the PTGRl activity is reducing the activity of 15-keto-prostaglandin. In embodiments, the PTGRl activity is reducing the activity of leukotriene B4. In embodiments, the PTGRl activity is binding NADP+.
  • a method of increasing the level of an acyl carnitine including contacting a cell with a substance (e.g., composition) capable of increasing the level of an acyl carnitine.
  • a substance e.g., composition
  • the substance (e.g., composition) capable of increasing the level of an acyl carnitine is a compound described herein.
  • the substance (e.g., composition) capable of increasing the level of an acyl carnitine is an oligonucleotide (e.g., DNA, RNA, or siRNA), antisense nucleic acid, protein (e.g., antibody), or compound (e.g., compound described herein).
  • the substance (e.g., composition) capable of increasing the level of an acyl carnitine is included in an effective amount.
  • the substance (e.g., composition) capable of increasing the level of an acyl carnitine is a deubiquitinase inhibitor (e.g., deubiquitinase inhibitor described herein, WP1130, ESI09, GW4604).
  • the acyl carnitine is C16:0 AC.
  • the method includes reducing mitochondrial respiration.
  • the method increases the level of activity of carnitine palmitoyltransferase 1 (CPT1) (e.g, compared to a control such as absence of the composition).
  • CPT1 carnitine palmitoyltransferase 1
  • a PTGRl protein covalently bonded to a PTGRl inhibitor (a PTGRl protein-PTGRl inhibitor complex).
  • the PTGRl is a human PTGRl (e.g., SEQ ID NO: l).
  • the PTGRl inhibitor is a compound described herein.
  • the PTGRl inhibitor is an oligonucleotide (e.g., DNA, RNA, or siRNA), antisense nucleic acid, protein (e.g., antibody, anti-PTGRl antibody, anti- PTGR1 binding antibody fragment), or compound (e.g., compound described herein).
  • the PTGRl inhibitor is provided in a therapeutically effective amount.
  • the PTGRl inhibitor contacts one or more amino acids corresponding to P48, M124, T128, A149, A153, V154, N217, C239, Y245, V271, or V272 of human PTGRl .
  • the PTGRl inhibitor covalently binds an amino acid corresponding to C239 in human PTGRl .
  • the PTGRl inhibitor contacts an amino acid corresponding to P48, M124, T128, A149, A153, V154, N217, Y245, V271, or V272of human PTGRl .
  • the PTGRl inhibitor covalently binds an amino acid corresponding to C239 in human PTGRl .
  • the PTGRl inhibitor contacts an amino acid corresponding to C239 in human PTGRl . In embodiments, the PTGRl inhibitor contacts an amino acid corresponding to P48 in human PTGRl . In embodiments, the PTGRl inhibitor contacts an amino acid corresponding to M124 in human PTGRl . In embodiments, the PTGRl inhibitor contacts an amino acid corresponding to T128 in human PTGRl . In embodiments, the PTGRl inhibitor contacts an amino acid corresponding to A149 in human PTGRl . In embodiments, the PTGRl inhibitor contacts an amino acid corresponding to A153 in human PTGRl . In embodiments, the PTGRl inhibitor contacts an amino acid corresponding to VI 54 in human PTGRl .
  • the PTGRl inhibitor contacts an amino acid corresponding to N217 in human PTGRl . In embodiments, the PTGRl inhibitor contacts an amino acid corresponding to Y245 in human PTGRl . In embodiments, the PTGRl inhibitor contacts an amino acid corresponding to V271 in human PTGRl . In embodiments, the PTGRl inhibitor contacts an amino acid corresponding to V272 in human PTGRl .
  • a PTGRl protein covalently bonded to a compound described herein.
  • the compound contacts one or more amino acids corresponding to P48, M124, T128, A149, A153, V154, N217, C239, Y245, V271, or V272 of human PTGRl .
  • the compound contacts one or more amino acids corresponding to P48, M124, T128, A149, A153, V154, N217, Y245, V271, or V272 of human PTGRl .
  • the compound contacts one or more amino acids corresponding to P48, M124, T128, A149, A153, N217, C239, Y245, V271, or V272 of human PTGRl . In embodiments, the compound contacts one or more amino acids corresponding to P48, M124, T128, A149, A153, N217, Y245, V271, or V272 of human PTGRl . In embodiments, the compound covalently binds an amino acid corresponding to C239 in human PTGRl . In embodiments, the compound contacts an amino acid
  • the compound contacts an amino acid corresponding to P48 in human PTGRl . In embodiments, the compound contacts an amino acid corresponding to M124 in human PTGRl . In embodiments, the compound contacts an amino acid corresponding to T128 in human PTGRl . In embodiments, the compound contacts an amino acid corresponding to A149 in human PTGRl .
  • the compound contacts an amino acid corresponding to A153 in human
  • the compound contacts an amino acid corresponding to VI 54 in human PTGRl . In embodiments, the compound contacts an amino acid corresponding to N217 in human PTGRl . In embodiments, the compound contacts an amino acid corresponding to Y245 in human PTGRl . In embodiments, the compound contacts an amino acid corresponding to V271 in human PTGRl . In embodiments, the compound contacts an amino acid corresponding to V272 in human PTGRl .
  • the compound is bonded to a cysteine residue of the PTGRl protein. In embodiments, the compound is covalently bonded to a cysteine residue of the
  • the compound is reversibly covalently bonded to a cysteine residue of the PTGRl protein. In embodiments, the compound is irreversibly covalently bonded to a cysteine residue of the PTGRl protein. In embodiments, the cysteine residue corresponds to C239 of human PTGRl .
  • the PTGRl protein is covalently bonded (e.g., reversibly or irreversibly) to a portion (e.g., the product of an electrophilic reaction with C239 of human PTGRl or cysteine corresponding to C239 of human PTGRl) of a compound described herein (e.g., portion of a PTGRl inhibitor or portion (e.g., through reacted electrophilic
  • the PTGRl inhibitor is capable of contacting one or more amino acids corresponding to P48, M124, T128, A149, A153, V154, N217, C239, Y245, V271, or V272 of SEQ ID NO: 1. In embodiments, the PTGRl inhibitor is capable of contacting one or more amino acids corresponding to P48, M124, T128, A149, A153, V154, N217, C239, Y245, V271, or V272 of SEQ ID NO: 1. In embodiments, the PTGRl inhibitor covalently binds an amino acid corresponding to C239 in SEQ ID NO: 1.
  • the PTGRl inhibitor is capable of contacting an amino acid corresponding to P48, M124, T128, A149, A153, V154, N217, Y245, V271, or V272of SEQ ID NO: l .
  • the PTGRl inhibitor covalently binds an amino acid corresponding to C239 in SEQ ID NO: 1.
  • the PTGRl inhibitor is capable of contacting an amino acid corresponding to C239 in SEQ ID NO: 1.
  • the PTGRl inhibitor is capable of contacting an amino acid corresponding to P48 in SEQ ID NO: 1.
  • the PTGRl inhibitor is capable of contacting an amino acid corresponding to Ml 24 in SEQ ID NO: 1.
  • the PTGRl inhibitor is capable of contacting an amino acid corresponding to T128 in SEQ ID NO: l . In embodiments, the PTGRl inhibitor is capable of contacting an amino acid corresponding to A149 in SEQ ID NO: 1. In embodiments, the PTGRl inhibitor is capable of contacting an amino acid corresponding to A153 in SEQ ID NO: l . In embodiments, the PTGRl inhibitor is capable of contacting an amino acid corresponding to VI 54 in SEQ ID NO: l . In embodiments, the PTGRl inhibitor is capable of contacting an amino acid corresponding to N217 in SEQ ID NO: 1. In embodiments, the PTGRl inhibitor is capable of contacting an amino acid corresponding to Y245 in SEQ ID NO: 1.
  • the PTGRl inhibitor is capable of contacting an amino acid corresponding to V271 in SEQ ID NO: l . In embodiments, the PTGRl inhibitor is capable of contacting an amino acid corresponding to V272 in SEQ ID NO: 1.
  • the PTGRl inhibitor contacts one or more amino acids
  • the PTGRl inhibitor covalently binds an amino acid corresponding to C239 in SEQ ID NO: 1.
  • the PTGRl inhibitor contacts an amino acid corresponding to P48, M124, T128, A149, A153, V154, N217, Y245, V271, or V272of SEQ ID NO: 1.
  • the PTGRl inhibitor covalently binds an amino acid corresponding to C239 in SEQ ID NO: 1.
  • the PTGRl inhibitor contacts an amino acid corresponding to C239 in SEQ ID NO: l . In embodiments, the PTGRl inhibitor contacts an amino acid corresponding to P48 in SEQ ID NO: 1. In embodiments, the PTGRl inhibitor contacts an amino acid corresponding to M124 in SEQ ID NO: 1. In embodiments, the PTGRl inhibitor contacts an amino acid corresponding to T 128 in SEQ ID NO: 1. In embodiments, the PTGRl inhibitor contacts an amino acid corresponding to A149 in SEQ ID NO: 1. In embodiments, the PTGRl inhibitor contacts an amino acid corresponding to Al 53 in SEQ ID NO: l . In embodiments, the PTGRl inhibitor contacts an amino acid
  • the PTGRl inhibitor contacts an amino acid corresponding to N217 in SEQ ID NO: 1. In embodiments, the PTGRl inhibitor contacts an amino acid corresponding to Y245 in SEQ ID NO: 1. In embodiments, the PTGRl inhibitor contacts an amino acid corresponding to V271 in SEQ ID NO: 1. In embodiments, the PTGRl inhibitor contacts an amino acid corresponding to V272 in SEQ ID NO: l .
  • a PTGRl protein covalently bonded to a compound described herein.
  • the compound contacts one or more amino acids corresponding to P48, M124, T128, A149, A153, V154, N217, C239, Y245, V271, or V272 of SEQ ID NO: 1.
  • the compound contacts one or more amino acids corresponding to P48, M124, T128, A149, A153, V154, N217, Y245, V271, or V272 of SEQ ID NO: 1.
  • the compound contacts one or more amino acids corresponding to P48, M124, T128, A149, A153, N217, C239, Y245, V271, or V272 of SEQ ID NO: 1. In embodiments, the compound contacts one or more amino acids corresponding to P48, Ml 24, T128, A149, A153, N217, Y245, V271, or V272 of SEQ ID NO: l . In embodiments, the compound covalently binds an amino acid corresponding to C239 in SEQ ID NO: 1. In embodiments, the compound contacts an amino acid corresponding to C239 in SEQ ID NO: 1. In embodiments, the compound contacts an amino acid corresponding to P48 in SEQ ID NO: 1. In embodiments, the compound contacts an amino acid corresponding to M124 in SEQ ID NO: 1. In embodiments, the compound contacts an amino acid corresponding to T128 in SEQ ID NO: l . In embodiments, the compound contacts an amino acid
  • the compound contacts an amino acid corresponding to A149 in SEQ ID NO: 1.
  • the compound contacts an amino acid corresponding to A153 in SEQ ID NO: l .
  • the compound contacts an amino acid corresponding to VI 54 in SEQ ID NO: l .
  • the compound contacts an amino acid corresponding to N217 in SEQ ID NO: 1.
  • the compound contacts an amino acid corresponding to Y245 in SEQ ID NO: 1.
  • the compound contacts an amino acid corresponding to V271 in SEQ ID NO: l .
  • the compound contacts an amino acid corresponding to V272 in SEQ ID NO: l .
  • a PTGR1 protein covalently bonded to a compound described herein.
  • the compound is capable of contacting one or more amino acids corresponding to P48, M124, T128, A149, A153, V154, N217, C239, Y245, V271, or V272 of SEQ ID NO: 1.
  • the compound is capable of contacting one or more amino acids corresponding to P48, M124, T128, A149, A153, V154, N217, Y245, V271, or V272 of SEQ ID NO: 1.
  • the compound is capable of contacting one or more amino acids corresponding to P48, M124, T128, A149, A153, N217, C239, Y245, V271, or V272 of SEQ ID NO: 1. In embodiments, the compound is capable of contacting one or more amino acids corresponding to P48, M124, T128, A149, A153, N217, Y245, V271, or V272 of SEQ ID NO: 1. In embodiments, the compound is capable of covalently binding an amino acid corresponding to C239 in SEQ ID NO: 1. In embodiments, the compound is capable of contacting an amino acid corresponding to C239 in SEQ ID NO: 1.
  • the compound is capable of contacting an amino acid corresponding to P48 in SEQ ID NO: 1. In embodiments, the compound is capable of contacting an amino acid corresponding to M124 in SEQ ID NO: l . In embodiments, the compound is capable of contacting an amino acid corresponding to T128 in SEQ ID NO: l . In embodiments, the compound is capable of contacting an amino acid corresponding to A149 in SEQ ID NO: 1. In embodiments, the compound is capable of contacting an amino acid corresponding to A153 in SEQ ID NO: l . In embodiments, the compound is capable of contacting an amino acid corresponding to VI 54 in SEQ ID NO: l .
  • the compound is capable of contacting an amino acid corresponding to N217 in SEQ ID NO: 1. In embodiments, the compound is capable of contacting an amino acid corresponding to Y245 in SEQ ID NO: 1. In embodiments, the compound is capable of contacting an amino acid corresponding to V271 in SEQ ID NO: l . In embodiments, the compound is capable of contacting an amino acid corresponding to V272 in SEQ ID NO: 1. [0246] In embodiments, the compound is bonded to a cysteine residue of the PTGRl protein. In embodiments, the compound is covalently bonded to a cysteine residue of the PTGRl protein.
  • the compound is reversibly covalently bonded to a cysteine residue of the PTGRl protein. In embodiments, the compound is irreversibly covalently bonded to a cysteine residue of the PTGRl protein. In embodiments, the cysteine residue corresponds to C239 of SEQ ID NO: 1.
  • the PTGRl protein is covalently bonded (e.g., reversibly or irreversibly) to a portion (e.g., the product of an electrophilic reaction with C239 of SEQ ID NO: 1 or cysteine corresponding to C239 of SEQ ID NO: 1) of a compound described herein (e.g., portion of a PTGRl inhibitor or portion of a compound described herein).
  • a PTGRl protein e.g., human PTGRl
  • a PTGRl inhibitor e.g., PTGRl inhibitor, compound described herein, or a portion of a compound described herein.
  • the PTGRl protein (e.g., human PTGRl) is covalently bonded to a PTGRl inhibitor (e.g., compound described herein or a portion of a compound described herein).
  • the PTGRl protein (e.g., human PTGRl) is irreversibly covalently bonded to a PTGRl inhibitor (e.g., compound described herein or a portion of a compound described herein).
  • the PTGRl protein (e.g., human PTGRl) is reversibly covalently bonded to a PTGRl inhibitor (e.g., compound described herein or a portion of a compound described herein).
  • the PTGRl protein (e.g., human PTGRl) is covalently bonded to a portion of a PTGRl inhibitor (e.g., compound described herein).
  • the PTGRl protein (e.g., human PTGRl) is irreversibly covalently bonded to a portion of a PTGRl inhibitor (e.g., compound described herein).
  • the PTGRl protein (e.g., human PTGRl) is reversibly covalently bonded to a portion of a PTGRl inhibitor (e.g., compound described herein).
  • the PTGRl inhibitor e.g., compound described herein
  • a cysteine residue e.g., C239 of human PTGRl or cysteine corresponding to C239 of human PTGRl
  • the PTGRl protein e.g., human PTGRl
  • the portion (e.g., the product of an electrophilic reaction with C239 of human PTGRl or cysteine corresponding to C239 of human PTGRl) of a PTGRl inhibitor (e.g., compound described herein) is bonded to a cysteine residue (e.g., C239 of human PTGRl or cysteine corresponding to C239 of human PTGRl) of the PTGRl protein (e.g., human PTGRl).
  • the PTGRl protein e.g., SEQ ID NO: 1
  • a PTGRl inhibitor e.g., compound described herein or a portion of a compound described herein.
  • the PTGRl protein (e.g., SEQ ID NO: l) is irreversibly covalently bonded to a PTGRl inhibitor (e.g., compound described herein or a portion of a compound described herein).
  • the PTGRl protein (e.g., SEQ ID NO: l) is reversibly covalently bonded to a PTGRl inhibitor (e.g., compound described herein or a portion of a compound described herein).
  • the PTGRl protein (e.g., SEQ ID NO: 1) is covalently bonded to a portion of a PTGRl inhibitor (e.g., compound described herein).
  • the PTGRl protein (e.g., SEQ ID NO: l) is irreversibly covalently bonded to a portion of a PTGRl inhibitor (e.g., compound described herein).
  • the PTGRl protein (e.g., SEQ ID NO: 1) is reversibly covalently bonded to a portion of a PTGRl inhibitor (e.g., compound described herein).
  • the PTGRl inhibitor e.g., compound described herein
  • a cysteine residue e.g., C239 of SEQ ID NO: 1 or cysteine corresponding to C239 of SEQ ID NO: 1 of the PTGRl protein (e.g., SEQ ID NO: 1).
  • the portion (e.g., the product of an electrophilic reaction with C239 of SEQ ID NO: 1 or cysteine corresponding to C239 of SEQ ID NO: 1) of a PTGRl inhibitor is bonded to a cysteine residue (e.g., C239 of SEQ ID NO: 1 or cysteine corresponding to C239 of SEQ ID NO: 1) of the PTGRl protein (e.g., SEQ ID NO: l).
  • the PTGRl protein covalently bonded to a PTGRl inhibitor or compound described herein is the product of a reaction between the PTGRl protein and a PTGRl inhibitor or compound described herein (e.g., a reaction between the electrophilic group and a cysteine of the PTGRl protein).
  • a reaction between the PTGRl protein and a PTGRl inhibitor or compound described herein e.g., a reaction between the electrophilic group and a cysteine of the PTGRl protein.
  • the covalently bonded PTGRl protein and PTGRl inhibitor are the remnants of the reactant PTGRl protein and PTGRl inhibitor or compound, wherein each reactant now participates in the covalent bond between the PTGRl protein and PTGRl inhibitor or compound.
  • the remnant of the alkenyl containing substituent is a linker including a covalent bond between the PTGRl protein and the remainder of the compound described herein.
  • the PTGRl inhibitor e.g., compound described herein
  • the PTGRl inhibitor forms a remnant of the pre-reacted PTGRl inhibitor (e.g., compound described herein) wherein a bond connects the remnant of the PTGRl inhibitor (e.g., compound described herein) to the remnant of the PTGRl protein (e.g., cysteine sulfur, sulfur of amino acid corresponding to C239 of human PTGRl, sulfur of C239 of human PTGRl (e.g., SEQ ID NO: l)).
  • cysteine sulfur sulfur of amino acid corresponding to C239 of human PTGRl
  • sulfur of C239 of human PTGRl e.g., SEQ ID NO: l
  • the remnant of the PTGRl inhibitor may also be called a portion of the PTGRl inhibitor.
  • the remnant of the alkenyl containing moiety is a linker selected from a bond, -S(0) 2 -, - H-, -0-, -S-, -C(O)-, -C(0) H-, - HC(O)-, - HC(0) H-, - HC(0) H-, -C(0)0-, -OC(O)-, -CH 2 H-, substituted (e.g., substituted with a substituent group, a size- limited substituent group, or lower substituent group) or unsubstituted alkylene (e.g., Ci-Cs, Ci-C 6 , C1-C4, or Ci-C 2 ), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkylene (e.g., Ci-C
  • the PTGRl protein covalently bonded to a PTGRl inhibitor may have the formula: ? wherein S is the sulfur of a PTGRl protein cysteine
  • the PTGRl protein covalently bonded to a PTGRl inhibitor may have the formula:
  • S is the sulfur of a PTGRl protein cysteine (e.g., corresponding to C239 of human PTGRl), which is bonded to the remainder of the PTGRl protein and wherein R 1 R 1 2 , R 1 3 , R 1 4 , R 1 5 , R 2 R 2 2 , R 2 3 , R 2 4 , and R 2 5 are as described herein.
  • a PTGRl protein cysteine e.g., corresponding to C239 of human PTGRl
  • R 1 R 1 2 , R 1 3 , R 1 4 , R 1 5 , R 2 R 2 2 , R 2 3 , R 2 4 , and R 2 5 are as described herein.
  • the PTGRl protein covalently bonded to a PTGRl inhibitor may have the formula:
  • S is the sulfur of a PTGRl protein cysteine (e.g., corresponding to C239 of human PTGRl, SEQ ID NO: 1), which is bonded to the remainder of the PTGRl protein and wherein R 1 2 , R 1 3 , R 1 5 , and R 2 3 are as described herein.
  • a PTGRl protein cysteine e.g., corresponding to C239 of human PTGRl, SEQ ID NO: 1
  • R 1 2 , R 1 3 , R 1 5 , and R 2 3 are as described herein.
  • the PTGRl protein covalently bonded to a PTGRl inhibitor may have the formula:
  • Embodiment PI A compound having the formula:
  • R 1 is independently halogen, -CX ⁇ , -CHX ⁇ , -CH2X 1 , -OCX ⁇ , - OCH2X 1 , -OCHX ⁇ , -CN, -SOniR 1D , -SOvi R 1A R 1B , - HC(0) R 1A R 1B , -N(0) m i, - R 1A R 1B , -C(0)R 1C , -C(0)-OR lc , -C(0) R 1A R 1B , -OR 1D , - R 1A S0 2 R 1D , - R 1A C(0)R 1C , - R 1A C(0)0 R 1C , - R 1A 0R 1C , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalky
  • zl is an integer from 0 to 5;
  • R 2 is independently halogen, -CX 2 3 , -CHX 2 2 , -CH 2 X 2 , -OCX 2 3 , - OCH2X 2 , -OCHX 2 2, -CN, -SO existence2R 2D , -SO v2 NR 2A R 2B , -NHC (0)NR 2A R 2B , -N(0) m2 , -NR 2A R 2B , -C(0)R 2C , -C(0)-OR 2C , -C(0)NR 2A R 2B , -OR 2D , -NR 2A S0 2 R 2D , -NR 2A C(0)R 2C , -NR 2A C(0)0 R 2C , -NR 2A OR 2C , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubsti
  • z2 is an integer from 0 to 5;
  • Each R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , and R 2D is independently hydrogen, -CX 3 , -CN, -COOH, -CONH2, -CHX 2 , -CH 2 X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or
  • R 1A and R 1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R and R substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
  • each X, X 1 , and X 2 is independently -F, -CI, -Br, or -I;
  • nl and n2 are independently an integer from 0 to 4.
  • nl, m2, vl, and v2 are independently an integer from 1 to 2.
  • Embodiment P2 The compound of embodiment PI having the formula:
  • R u , R 1 2 , R 1 3 , R 1 4 , and R 1 5 are independently hydrogen, halogen, -CX ⁇ , -
  • R 2 - 1 , R 2 2 , R 2 3 , R 2 4 , and R 2 5 are independently hydrogen, halogen, -CX 2 3 , - CHX 2 2, -CH2X 2 , -OCX 2 3 , -
  • Embodiment P3 The compound of embodiment P2 having the formula:
  • Embodiment P4 The compound of one of embodiments P2 to P3, wherein R 1 2 is substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl; R 1 3 is -OCX ⁇ , - OCH2X 1 , -OCHX ⁇ , -OR 1D , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R 1 5 is -OCX ⁇ , -OCH2X 1 , -OCHX ⁇ , -OR 1D , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; and R 2 3 is -OCX 2 3 , -OCH2X 2 , -OCHX 2 2 , -OR 2D , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. [0256] Embodiment P5. The compound
  • R 1 3 is -OR 1D ;
  • R 1 5 is -OR 1D ;
  • R 2 3 is -OR 2D ; and each R 1D and R 2D is independently hydrogen, -CX 3 , -CHX 2 , -CH 2 X, substituted or unsubstituted alkyl.
  • Embodiment P6 The compound of embodiment P4, wherein R 1 2 is
  • R 1 3 is -OR 1D ;
  • R 1 5 is -OR 1D ;
  • R 2 3 is -OR 2D ; and each R 1D and R 2D is independently hydrogen or substituted or unsubstituted Ci-Cs alkyl.
  • Embodiment P7 The compound of embodiment P4, wherein R 1 2 is
  • Embodiment P8 The compound of embodiment P4, wherein R 1 2 is
  • Embodiment P9 The compound of embodiment P4, wherein R 1 2 has the formula ; R 1 3 is -OH; R 1 5 is -OR 1D ; R 2 3 is -OH; and R 1D is independently unsubstituted C1-C2 alkyl.
  • Embodiment PI 0. The compound of one of embodiments PI to P9, wherein the compound is not licochalcone A.
  • Embodiment PI 1 A pharmaceutical composition comprising a prostaglandin reductase 1 (PTGRl) inhibitor and a pharmaceutically acceptable excipient.
  • PTGRl prostaglandin reductase 1
  • Embodiment P12 A pharmaceutical composition comprising a compound of one of embodiments PI to P10 and a pharmaceutically acceptable excipient.
  • Embodiment P13 A method of inhibiting prostaglandin reductase 1 (PTGRl) activity, said method comprising contacting the PTGRl protein with an effective amount of a prostaglandin reductase 1 (PTGRl) inhibitor.
  • PTGRl prostaglandin reductase 1
  • Embodiment P14 The method of embodiment PI 3, wherein the prostaglandin reductase 1 (PTGRl) inhibitor is an oligonucleotide (e.g., siRNA or shRNA), protein (e.g., antibody), or compound.
  • Embodiment PI 5 The method of embodiment PI 4, wherein the prostaglandin reductase 1 (PTGRl) inhibitor contacts one or more amino acids corresponding to P48, M124, T128, A149, A153, V154, N217, C239, Y245, V271, or V272 of human PTGRl .
  • PTGRl prostaglandin reductase 1
  • Embodiment PI 6 The method of embodiment PI 4, wherein the prostaglandin reductase 1 (PTGRl) inhibitor contacts one or more amino acids corresponding to P48, M124, T128, A149, A153, N217, Y245, V271, or V272 of human PTGRl .
  • Embodiment PI 7. A method of inhibiting prostaglandin reductase 1 (PTGRl) activity, said method comprising contacting the PTGRl protein with an effective amount of a compound of one of embodiments PI to PI 0.
  • Embodiment PI 8 The method of embodiment PI 7, wherein the compound is covalently bonded to the amino acid corresponding to C239 of human PTGRl .
  • Embodiment PI 9. The method of embodiment PI 7, wherein the compound contacts one or more amino acids corresponding to P48, M124, T128, A149, A153, V154, N217, C239, Y245, V271, or V272 of human PTGRl .
  • Embodiment P20 The method of one of embodiments P13 to PI 9, wherein the PTGRl activity is reducing a 15-keto-prostaglandin or leukotriene B4.
  • Embodiment P21 The method of one of embodiments P13 to PI 9, wherein the PTGRl activity is binding NADP+.
  • Embodiment P22 A method of treating cancer, said method comprising administering to a subject in need thereof an effective amount of a prostaglandin reductase 1 (PTGRl) inhibitor.
  • PTGRl prostaglandin reductase 1
  • Embodiment P23 A method of treating cancer, said method comprising administering to a subject in need thereof an effective amount of a compound of one of embodiments PI to P10.
  • Embodiment P24 The method of one of embodiments P22 to P23, wherein the cancer is lung cancer, prostate cancer, or breast cancer.
  • Embodiment P25 The method of one of embodiments P22 to P23, wherein the cancer is triple negative breast cancer.
  • Embodiment P26 A PTGRl protein covalently bonded to a prostaglandin reductase 1 (PTGRl) inhibitor.
  • Embodiment P27 A PTGRl protein covalently bonded to a compound of one of embodiments PI to P10 through the reacted residue of an electrophilic group.
  • Embodiment P28 The PTGRl protein of embodiment P27, wherein the compound is bonded to a cysteine residue of the protein.
  • Embodiment P29 The PTGRl protein of embodiment P27, covalently bonded to a portion of a compound of one of embodiments PI to P10.
  • Embodiment P30 The PTGRl protein of embodiment P27, irreversibly covalently bonded to a portion of a compound of one of embodiments PI to P10.
  • Embodiment P31 The PTGRl protein of one of embodiments P27 to P30, wherein the compound or portion of the compound is covalently bonded to an amino acid corresponding to C239 of human PTGRl .
  • Embodiment 1 A method of inhibiting prostaglandin reductase 1 (PTGRl) activity, said method comprising contacting a PTGRl protein with an effective amount of a prostaglandin reductase 1 (PTGRl) inhibitor, wherein said PTGRl inhibitor contacts one or more amino acids corresponding to P48, M124, T128, A149, A153, V154, N217, C239,
  • PTGRl inhibitor is covalently bonded to the amino acid corresponding to C239 of SEQ ID NO: 1, thereby forming a PTGRl protein covalently bonded to said PTGRl inhibitor.
  • Embodiment 2 The method of embodiment 1, wherein the prostaglandin
  • reductase 1 (PTGRl) inhibitor has the formula: (I), wherein, R 1 is independently halogen, -CX ⁇ , -CHX ⁇ , -CH2X 1 , -OCX ⁇ , - OCH2X 1 , -OCHX ⁇ , -CN, -SOniR 1D , -SOvi R 1A R 1B , - HC(0) R 1A R 1B , -N(0) m i, - R 1A R 1B , -C(0)R 1C , -C(0)-OR l c , -C(0) R 1A R 1B , -OR 1D , - R 1A S0 2 R 1D , - R 1A C(0)R 1C , - R 1A C(0)0 R 1 C , - R 1A 0R 1C , -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or
  • heterocycloalkyl substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl
  • two adjacent R 1 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • zl is an integer from 0 to 5;
  • R 2 is independently halogen, -CX 2 3 , -CHX 2 2 , -CH 2 X 2 , -OCX 2 3 , - OCH2X 2 , -OCHX 2 2, -CN, -SO existence2R 2D , -SO v2 NR 2A R 2B , -NHC (0)NR 2A R 2B , -N(0) m2 , -NR 2A R 2B , -C(0)R 2C , -C(0)-OR 2C , -C(0)NR 2A R 2B , -OR 2D , -NR 2A S0 2 R 2D , -NR 2A C(0)R 2C , -NR 2A C(0)0 R 2C , -NR 2A OR 2C , -N 3 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
  • heterocycloalkyl substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl
  • two adjacent R 2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • z2 is an integer from 0 to 5;
  • Each R 1A , R 1B , R 1 C , R 1D , R 2A , R 2B , R 2C , and R 2D is independently hydrogen, -CX 3 , -CN, -COOH, -CONH2, -CHX 2 , -CH 2 X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or
  • R 1A and R 1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
  • R 2A and R 2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
  • each X, X 1 , and X 2 is independently -F, -CI, -Br, or -I;
  • nl and n2 are independently an integer from 0 to 4.
  • Embodiment 3 A method of inhibiting prostaglandin reductase 1 (PTGR1) activity, said method comprising contacting a PTGR1 protein with an effective amount of a
  • R 1 is independently halogen, -CX ⁇ , -CHX ⁇ , -CH2X 1 , -OCX ⁇ , - OCH2X 1 , -OCHX ⁇ , -CN, -SOniR 1D , -SO v i R 1A R 1B , - HC(0) R 1A R 1B , -N(0) m i, - R 1A R 1B , -C(0)R 1C , -C(0)-OR lc , -C(0) R 1A R 1B , -OR 1D , - R 1A S0 2 R 1D , - R 1A C(0)R 1C , - R 1A C(0)0 R 1C , - R 1A 0R 1C , -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstit
  • heterocycloalkyl substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl
  • two adjacent R 1 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • zl is an integer from 0 to 5;
  • R 2 is independently halogen, -CX 2 3 , -CHX 2 2 , -CH 2 X 2 , -OCX 2 3 , - OCH2X 2 , -OCHX 2 2, -CN, -SO existence2R 2D , -SO v2 NR 2A R 2B , -NHC (0)NR 2A R 2B , -N(0) m2 , -NR 2A R 2B , -C(0)R 2C , -C(0)-OR 2C , -C(0)NR 2A R 2B , -OR 2D , -NR 2A S0 2 R 2D , -NR 2A C(0)R 2C , -NR 2A C(0)0 R 2C , -NR 2A OR 2C , -N 3 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
  • heterocycloalkyl substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl
  • two adjacent R 2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • z2 is an integer from 0 to 5;
  • Each R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , and R 2D is independently hydrogen, -CX 3 , -CN, -COOH, -CONH2, -CHX 2 , -CH 2 X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or
  • R 1A and R 1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
  • R 2A and R 2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
  • each X, X 1 , and X 2 is independently -F, -CI, -Br, or -I;
  • nl and n2 are independently an integer from 0 to 4.
  • nl, m2, vl, and v2 are independently an integer from 1 to 2.
  • Embodiment 4 The method of embodiment 3, wherein the compound is capable of covalently bonding to the amino acid corresponding to C239 of SEQ ID NO: 1.
  • Embodiment 5 The method of embodiments 3 or 4, wherein the compound is capable of contacting one or more amino acids corresponding to P48, M124, T128, A149, A153, V154, N217, C239, Y245, V271, or V272 of SEQ ID NCv l .
  • Embodiment 6 The method of one of embodiments 1 to 5, wherein the PTGR1 activity is reducing the activity of 15-keto-prostaglandin or leukotriene B4.
  • Embodiment 7 The method of one of embodiments 1 to 5, wherein the PTGR1 activity is binding NADP+.
  • Embodiment 8 The method of any one of embodiments 3 to 7, wherein the
  • R u , R 1 2 , R 1 3 , R 1 4 , and R 1 5 are independently hydrogen, halogen, -CX X 3 , - CHX 1 !, -CH2X 1 , -OCX , -OCH2X 1 , -OCHX ⁇ , -CN, -SO n iR 1D , -SO v iNR 1A R 1B ,
  • R 2 - 1 , R 2 2 , R 2 3 , R 2 4 , and R 2 5 are independently hydrogen, halogen, -CX 2 3 , - CHX 2 2, -CH2X 2 , -OCX 2 3 , -OCH2X 2 , -OCHX 2 2, -CN, -SO ⁇ R 20 , -SO v2 NR 2A R 2B ,
  • Embodiment 9 The method of embodiment 8, wherein the compound has the
  • Embodiment 10 The method of embodiments 8 or 9, wherein: R 1 2 is
  • R 1 3 is independently -OCXS, -OCH2X 1 , -OCHX ⁇ , -OR 1D , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl
  • R 1 5 is independently -OCX ⁇ , - OCH2X 1 , -OCHX ⁇ , -OR 1D , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl
  • R 2 3 is independently -OCX 2 3 , -OCH2X 2 , -OCHX 2 2 , -OR 2D , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
  • Embodiment 11 The method of embodiments 8 or 9, wherein R 1 2 is
  • R 1 3 is independently -OR 1D ;
  • R 1 5 is independently -OR 1D ;
  • R 2 3 is independently -OR 2D ; and each R 1D and R 2D is independently
  • Embodiment 12 The method of embodiments 8 or 9, wherein R 1 2 is
  • R 1 3 is independently -OR 1D ;
  • R 1 5 is
  • Embodiment 13 The method of embodiments 8 or 9, wherein R 1 2 is
  • R 2 3 is independently -OH; and R 1D is independently hydrogen or unsubstituted C1-C4 alkyl.
  • Embodiment 14 The method of embodiments 8 or 9, wherein R 1 2 is
  • R 2 3 is independently -OH; and R 1D is independently unsubstituted Ci-
  • Embodiment 15 The method of embodiments 8 or 9, wherein R 1 2 independently has the ; R 1 3 is independently -OH; R 1 5 is independently -OR 1D ; R 2 3 is independently -OH; and R 1D is independently unsubstituted C 1-C2 alkyl.
  • Embodiment 16 The method of any one of embodiments 3 to 15, wherein the compound is not licochalcone A.
  • Embodiment 17 A method of treating cancer, said method comprising administering to a subject in need thereof an effective amount of a prostaglandin reductase 1 (PTGR1) inhibitor.
  • PTGR1 prostaglandin reductase 1
  • Embodiment 18 The method of embodiment 17, wherein the cancer is lung cancer, prostate cancer, or breast cancer.
  • Embodiment 19 The method of embodiment 17, wherein the cancer is triple negative breast cancer.
  • Embodiment 20 The method of any one of embodiments 17 to 19, said method comprising administering to a subject in need thereof an effective amount of a compound
  • R 1 is independently halogen, -CX ⁇ , -CHX ⁇ , -CH2X 1 , -OCX ⁇ , - OCH2X 1 , -OCHX ⁇ , -CN, -SOniR 1D , -SOvi R 1A R 1B , - HC(0) R 1A R 1B , -N(0) m i, - R 1A R 1B , -C(0)R 1C , -C(0)-OR l c , -C(0) R 1A R 1B , -OR 1D , - R 1A S0 2 R 1D , - R 1A C(0)R 1C , - R 1A C(0)0 R 1 C , - R 1A OR lc , -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
  • heterocycloalkyl substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl
  • two adjacent R 1 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • zl is an integer from 0 to 5;
  • R 2 is independently halogen, -CX 2 3 , -CHX 2 2 , -CH 2 X 2 , -OCX 2 3 , - OCH2X 2 , -OCHX 2 2, -CN, -SO existence2R 2D , -SO v2 NR 2A R 2B , -NHC (0)NR 2A R 2B , -N(0) m2 , -NR 2A R 2B , -C(0)R 2C , -C(0)-OR 2C , -C(0)NR 2A R 2B , -OR 2D , -NR 2A S0 2 R 2D , -NR 2A C(0)R 2C , -NR 2A C(0)0 R , - R OR , -N 3 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubsti
  • heterocycloalkyl substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl
  • two adjacent R 2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • z2 is an integer from 0 to 5;
  • Each R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , and R 2D is independently hydrogen, -CX 3 , -CN, -COOH, -CO H2, -CHX 2 , -CH 2 X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or
  • R 1A and R 1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
  • R 2A and R 2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
  • each X, X 1 , and X 2 is independently -F, -CI, -Br, or -I;
  • nl and n2 are independently an integer from 0 to 4.
  • nl, m2, vl, and v2 are independently an integer from 1 to 2;
  • Embodiment 21 The use of a compound for the preparation of a medicament for the treatment of cancer, wherein the compound has the formula:
  • zl is an integer from 0 to 5;
  • R 2 is independently halogen, -CX 2 3 , -CHX 2 2 , -CH 2 X 2 , -OCX 2 3 , -
  • heterocycloalkyl substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl
  • two adjacent R 2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • z2 is an integer from 0 to 5;
  • Each R , R , R , R , R , R , R , R , and R 2D is independently hydrogen, -CX 3 , -CN, -COOH, -CONH2, -CHX 2 , -CH 2 X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or
  • R 1A and R 1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
  • R 2A and R 2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
  • each X, X 1 , and X 2 is independently -F, -CI, -Br, or -I;
  • nl and n2 are independently an integer from 0 to 4.
  • nl, m2, vl, and v2 are independently an integer from 1 to 2, wherein the
  • heterocycloalkyl substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl
  • two adjacent R 1 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • zl is an integer from 0 to 5;
  • R 2 is independently halogen, -CX 2 3 , -CHX 2 2 , -CH 2 X 2 , -OCX 2 3 , - OCH2X 2 , -OCHX 2 2, -CN, -SO existence2R 2D , -SO v2 NR 2A R 2B , -NHC (0)NR 2A R 2B , -N(0) m2 , -NR 2A R 2B , -C(0)R 2C , -C(0)-OR 2C , -C(0)NR 2A R 2B , -OR 2D , -NR 2A S0 2 R 2D , -NR 2A C(0)R 2C , -NR 2A C(0)0 R 2C , -NR 2A OR 2C , -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
  • heterocycloalkyl substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl
  • two adjacent R 2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • z2 is an integer from 0 to 5;
  • Each R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , and R 2D is independently hydrogen, -CX 3 , -CN, -COOH, -CONH2, -CHX 2 , -CH 2 X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or
  • R 1A and R 1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
  • R 2A and R 2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
  • each X, X 1 , and X 2 is independently -F, -CI, -Br, or -I;
  • nl and n2 are independently an integer from 0 to 4.
  • nl, ml, vl, and v2 are independently an integer from 1 to 2.
  • Embodiment 23 The PTGR1 protein of embodiment 22, wherein the compound is bonded to a cysteine residue of the protein.
  • Embodiment 24 The PTGR1 protein of embodiment 22, irreversibly covalently bonded to the compound.
  • Embodiment 25 The PTGR1 protein of embodiment 22, wherein the compound or portion of the compound is covalently bonded to an amino acid corresponding to C239 of SEQ ID NO: l .
  • Embodiment 26 A pharmaceutical composition comprising a prostaglandin reductase 1 (PTGR1) inhibitor and a pharmaceutically acceptable excipient.
  • Embodiment 27 The pharmaceutical composition of embodiment 26, wherein
  • the PTGR1 inhibitor has the formula: (I), wherein,
  • R 1 is independently halogen, -CX ⁇ , -CHX ⁇ , -CH2X 1 , -OCX ⁇ , - OCH2X 1 , -OCHX ⁇ , -CN, -SOniR 1D , -SOvi R 1A R 1B , - HC(0) R 1A R 1B , -N(0) m i, - R 1A R 1B , -C(0)R 1C , -C(0)-OR l c , -C(0) R 1A R 1B , -OR 1D , - R 1A S0 2 R 1D , - R 1A C(0)R 1C , - R 1A C(0)0 R 1 C , - R 1A OR lc , -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
  • heterocycloalkyl substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl
  • two adjacent R 1 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • zl is an integer from 0 to 5;
  • R 2 is independently halogen, -CX 2 3 , -CHX 2 2 , -CH 2 X 2 , -OCX 2 3 , - OCH2X 2 , -OCHX 2 2, -CN, -SO existence2R 2D , -SO v2 NR 2A R 2B , -NHC (0)NR 2A R 2B , -N(0) m2 , -NR 2A R 2B , -C(0)R 2C , -C(0)-OR 2C , -C(0)NR 2A R 2B , -OR 2D , -NR 2A S0 2 R 2D , -NR 2A C(0)R 2C , -NR 2A C(0)0 R , - R OR , -N 3 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubsti
  • heterocycloalkyl substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl
  • two adjacent R 2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • z2 is an integer from 0 to 5;
  • Each R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , and R 2D is independently hydrogen, -CX 3 , -CN, -COOH, -CO H 2 , -CHX 2 , -CH 2 X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or
  • R 1A and R 1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
  • R 2A and R 2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
  • each X, X 1 , and X 2 is independently -F, -CI, -Br, or -I;
  • nl and n2 are independently an integer from 0 to 4.
  • nl, m2, vl, and v2 are independently an integer from 1 to 2.
  • Embodiment 28 A method of treating triple negative breast cancer, said method comprising administering to a subject in need thereof an effective amount of a compound
  • R 1 is independently halogen, -CX ⁇ , -CHX ⁇ , -CH2X 1 , -OCX ⁇ , - OCH2X 1 , -OCHX ⁇ , -CN, -SOniR 1D , -SOviNR 1A R 1B , -NHC(0)NR 1A R 1B , -N(0) m i, -NR 1A R 1B , -C(0)R 1C , -C(0)-OR lc , -C(0)NR 1A R 1B , -OR 1D , -NR 1A S0 2 R 1D , -NR 1A C(0)R 1C , -NR 1A C(0)0 R 1C , -NR 1A 0R 1C , -N 3 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstitute
  • heterocycloalkyl substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl
  • two adjacent R 1 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl
  • zl is an integer from 0 to 5;
  • R 2 is independently halogen, -CX 2 3 , -CHX 2 2 , -CH 2 X 2 , -OCX 2 3 , - OCH 2 X 2 , -OCHX 2 2, -CN, -SO existence2R 2D , -SO v2 R 2A R 2B , - HC(0) R 2A R 2B , -N(0) m2 , - R 2A R 2B , -C(0)R 2C , -C(0)-OR 2C , -C(0) R 2A R 2B , -OR 2D , - R 2A S0 2 R 2D , - R 2A C(0)R 2C , - R 2A C(0)0 R 2C , - R 2A OR 2C , -N 3 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substitute
  • heterocycloalkyl substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl
  • two adjacent R 2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • z2 is an integer from 0 to 5;
  • Each R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , and R 2D is independently hydrogen, -CX 3 , -CN, -COOH, -CONH2, -CHX 2 , -CH 2 X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or
  • R 1A and R 1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
  • R 2A and R 2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
  • each X, X 1 , and X 2 is independently -F, -CI, -Br, or -I;
  • nl and n2 are independently an integer from 0 to 4.
  • nl, m2, vl, and v2 are independently an integer from 1 to 2.
  • Embodiment 29 The method of embodiment 28, wherein the compound has the
  • R u , R 1 2 , R 1 3 , R 1 4 , and R 1 5 are independently hydrogen, halogen, -CX X 3 , - CHX ⁇ , -CH2X 1 , -OCX , -OCH2X 1 , -OCHX ⁇ , -CN, -SO n iR 1D , -SO v iNR 1A R 1B ,
  • R 2 - 1 , R 2 2 , R 2 3 , R 2 4 , and R 2 5 are independently hydrogen, halogen, -CX 2 3 , - CHX 2 2, -CH2X 2 , -OCX 2 3 , -OCH2X 2 , -OCHX 2 2, -CN, -SC R 20 , -SO v2 R 2A R 2B ,
  • Embodiment 30 The method of embodiment 28, wherein the compound has the
  • Embodiment 31 The method of embodiments 28 or 29, wherein: R 1 2 is independently substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl; R 1 3 is independently -OCXS, -OCH2X 1 , -OCHX ⁇ , -OR 1D , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R 1 5 is independently -OCX ⁇ , -
  • R 2 3 is independently -OCX 2 3 , -OCH2X 2 , -OCHX 2 2 , -OR 2D , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
  • Embodiment 32 The method of embodiments 28 or 29, wherein R 1 2 is independently unsubstituted alkyl; R 1 3 is independently -OR 1D ; R 1 5 is independently -OR 1D ; R 2 3 is independently -OR 2D ; and each R 1D and R 2D is independently
  • Embodiment 33 The method of embodiments 28 or 29, wherein R 1 2 is independently unsubstituted Ci-Cs alkyl; R 1 3 is independently -OR 1D ; R 1 5 is
  • R 1D and R 2D is independently hydrogen or substituted or unsubstituted Ci-Cs alkyl.
  • Embodiment 34 The method of embodiments 28 or 29, wherein R 1 2 is independently unsubstituted C1-C5 alkyl; R 1 3 is independently -OH; R 1 5 is independently -OR 1D ; R 2 3 is independently -OH; and R 1D is independently hydrogen or unsubstituted C1-C4 alkyl.
  • Embodiment 35 The method of embodiments 28 or 29, wherein R 1 2 is independently unsubstituted C1-C5 alkenyl; R 1 3 is independently -OH; R 1 5 is
  • R 2 3 is independently -OH; and R 1D is independently unsubstituted Ci- C 2 alkyl.
  • Embodiment 36 The method of embodiments 28 or 29, wherein R 1 2 independently has the formula ; R 1 3 is independently -OH; R 1 5 is
  • R 2 3 is independently -OH; and R 1D is independently unsubstituted Ci- C 2 alkyl.
  • Embodiment 37 The method of any one of embodiments 2, 3, 22, 27, or 28, wherein the compound has the the formula:
  • Embodiment 38 The method of an one of embodiments 2, 3, 22, 27, or 28,
  • Embodiment 39 The method of any one of embodiments 2, 3, 20, 21, 22, 27, or 28, wherein the compound has the the formula:
  • Embodiment 40 A compound covalently bonded to a sulfur atom of a cysteine residue of a PTGRl protein of the formula:
  • P-S- is said PTGRl protein and said sulfur atom;
  • R 1 is independently halogen, -CX ⁇ , -CHX ⁇ , -CH2X 1 , -OCX ⁇ , - OCH2X 1 , -OCHX ⁇ , -CN, -SOniR 1D , -SOvi R 1A R 1B , - HC(0) R 1A R 1B , -N(0) m i, - R 1A R 1B , -C(0)R 1C , -C(0)-OR l c , -C(0) R 1A R 1B , -OR 1D , - R 1A S0 2 R 1D , - R 1A C(0)R 1C , - R 1A C(0)0 R 1 C , - R 1A 0R 1C , -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubsti
  • heterocycloalkyl substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl
  • two adjacent R 1 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • zl is an integer from 0 to 5;
  • R 2 is independently halogen, -CX 2 3 , -CHX 2 2 , -CH 2 X 2 , -OCX 2 3 , - OCH2X 2 , -OCHX 2 2, -CN, -SO existence2R 2D , -SO v2 NR 2A R 2B , -NHC (0)NR 2A R 2B , -N(0) m2 , -NR 2A R 2B , -C(0)R 2C , -C(0)-OR 2C , -C(0)NR 2A R 2B , -OR 2D , -NR 2A S0 2 R 2D , -NR 2A C(0)R 2C , -NR 2A C(0)0 R 2C , -NR 2A OR 2C , -N 3 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
  • heterocycloalkyl substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl
  • two adjacent R 2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • z2 is an integer from 0 to 5;
  • Each R 1A , R 1B , R 1 C , R 1D , R 2A , R 2B , R 2C , and R 2D is independently hydrogen, -CX 3 , -CN, -COOH, -CONH2, -CHX 2 , -CH 2 X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or
  • R 1A and R 1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
  • R 2A and R 2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
  • each X, X 1 , and X 2 is independently -F, -CI, -Br, or -I;
  • nl and n2 are independently an integer from 0 to 4.
  • Embodiment 41 The PTGR1 protein of embodiment 40, irreversibly covalently bonded to the compound.
  • Embodiment 42 The PTGR1 protein of embodiments 40 or 41, wherein the compound or portion of the compound is covalently bonded to an amino acid corresponding to C239 of SEQ ID NCv l .
  • Embodiment 43 The PTGR1 protein of embodiment 40, wherein the PTGR1 protein is covalently bonded to a PTGR1 inhibitor having the formula:
  • Example 1 Mapping Novel Metabolic Nodes Targeted by Drugs that Impair Triple-Negative Breast Cancer Pathogenicity
  • T BCs Triple-negative breast cancers
  • chemoproteomic and metabolomic profiling to identify novel metabolic mechanisms for agents that impair T BC pathogenicity.
  • chemoproteomic profiling approaches we reveal that licochalcone A impairs TNBC pathogenicity, not through modulating estrogen receptor activity, but rather through inhibiting prostaglandin reductase 1, a metabolic enzyme involved in leukotriene B4 inactivation.
  • deubiquitinase inhibitors cause dramatic elevations in acyl carnitine levels, which impair mitochondrial respiration and contribute to TNBC pathogenic impairments.
  • Our results also showcase the utility of coupling drug screens with chemoproteomic and metabolomic profiling to uncover unique metabolic drivers
  • breast cancer cell-types such as estrogen/progesterone/HER2 receptor (ER/PR/HER2)-negative (triple-negative) breast cancers (TNBCs) that show poor prognosis and chemotherapy-resistance within breast tumors (3-5). Eliminating these breast cancer types are critical in reducing the mortality associated with breast cancer.
  • ER/PR/HER2 estrogen/progesterone/HER2 receptor
  • TNBCs triple-negative breast cancers
  • Dacomitinib Dacomitinib, polo-like kinase 1 (PLK) inhibitor BI6727, kinesin spindle protein (KSP) inhibitor Ispenisib, and Aurora kinase (AURK) inhibitor AT9283 (4,8-13).
  • Other compounds modulate protein targets that have been previously shown to be important in TNBCs including HDAC inhibitors SB939 and Romidepsin (14).
  • HDAC inhibitors SB939 and Romidepsin 14
  • the remaining compounds and their targets, while previously shown to be important in cancer are less understood in regards to their efficacy or roles in advanced-stage breast cancers or TNBCs. These include
  • deubiquitinase inhibitor WP1130 exchange proteins directly activated by cAMP isoform 1 (EPAC) inhibitor ESI-09, kinesin inhibitor ARQ 621, FXR activator GW4064, and the phytoestrogen natural product licochalcone A (15-19), and may represent promising therapeutic strategies for combating TNBCs.
  • cAMP isoform 1 (EPAC) inhibitor ESI-09 exchange proteins directly activated by cAMP isoform 1 (EPAC) inhibitor ESI-09
  • kinesin inhibitor ARQ 621 kinesin inhibitor
  • FXR activator GW4064 FXR activator GW4064
  • the phytoestrogen natural product licochalcone A (15-19), and may represent promising therapeutic strategies for combating TNBCs.
  • licochalcone A showed the greatest impairment (>95 %) in cell survival across the three TNBC cells tested here with a 50 % effective concentration (EC50) of 8.4 nM (FIG. 5).
  • the target of licochalcone A is classified as estrogen or progesterone receptors due to its previous characterization as an estrogenic flavonoid (17).
  • Licochalcone A is a flavonoid extracted from licorice root that has been shown to possess anti-inflammatory and anti- parasitic activity and has been tested on humans as an anti-inflammatory moisturizer (17,20- 25).
  • Licochalcone A belongs to a larger group of natural products known as chalcones characterized by their aromatic enone structures (FIG. 2A). These enones can potentially undergo Michael addition to cysteine thiols on proteins to modulate protein function.
  • FOG. 2A aromatic enone structures
  • IsoTOP-ABPP isotopic tandem orthogonal proteolysis-enabled activity-based protein profiling
  • probe-labeled proteins with isotopically light (for control) or heavy (for licochalcone-treated) handles bearing a biotin for avidin-enrichment and a TEV protease recognition sequence by copper- catalyzed azide-alkyne cycloaddition (CuAAC) for subsequent TEV protease release of probe-modified peptides for quantitative proteomic analysis of light to heavy peptide ratios (FIG. 2B).
  • CuAAC copper- catalyzed azide-alkyne cycloaddition
  • Leukotriene B4 through stimulating leukotriene B4 receptor BLT1, has also been shown to fuel TGF- -mediated proliferation in breast cancer cells (32).
  • C239 of PTGRl represents the binding region for NADP+, required for the reductase catalytic activity of this enzyme (33) (FIG. 2D), suggesting that licochalcone A binding to this site would displace NADP+ binding and inhibit PTGRl activity.
  • LPE lysphosphatidyl ethanolamines
  • LPC 06:0 lysophosphatidyl choline
  • LPCe C18:0e lysophosphatidylcholine-ether
  • ACs are metabolites generated by carnitine palmitoyltranf erase 1 (CPTl) at the mitochondrial membrane to import fatty acids into the mitochondria for fatty acid oxidation (34).
  • CPTl carnitine palmitoyltranf erase 1
  • the compound library consisting of 424 compounds at 10 mM in DMSO was purchased from Selleck Chemicals. IAyne was obtained from CHESS Gmbh. Heavy and light TEV-biotin tags were synthesized per previously described methods (28,38). Palmitoyl carnitine was obtained from Sigma-Aldrich and resuspended in deionized water to 100 mM stock. Lysophosphatidyl ethanolamine was obtained from Avanti Polar Lipids and resuspended in 2: 1 chloroform:methanol to a 10 mM stock.
  • HCC38, HCC70, and HEK293T cells were obtained from the American Type Culture Collection (ATCC).
  • 231MFP cells were cultured in L15 (HyClone) medium containing 10% FBS, supplemented with 2% glutamine (200 mM stock), and maintained at 37°C with 0% CO2.
  • HCC38 and HCC70 cells were cultured in RPMI (Gibco) medium containing 10% FBS, supplemented with 2% glutamine (200 mM stock), and maintained at 37°C with 5% CO2.
  • HEK293T cells were cultured in DMEM (Corning) containing 10% FBS, supplemented with 2% glutamine (200 mM stock) and maintained at 37°C with 5% C0 2 .
  • HCC38 cells and HCC70 were also performed as above but were seeded with 20,000 and 30,000 cells, respectively.
  • Cell proliferation assays were performed as above but cells were seeded (20,000 for 231MFP cells) and treated in medium containing FBS.
  • IsoTOP-ABPP IsoTOP-ABPP studies were done as previously reported (26,28). Proteome samples diluted in PBS were treated with Withaferin A or vehicle for 30 min at 37°C. Then, IAyne labeling was performed for 1 h at room temperature.
  • CuAAC was used by sequential addition of tris(2-carboxyethyl)phosphine (1 mM, Sigma), tris[(l-benzyl-lH-l,2,3- triazol-4-yl)methyl]amine (34 ⁇ , Sigma), copper (II) sulfate (1 mM, Sigma), and biotin- linker-azide, the linker functionalized with a TEV protease recognition sequence along with an isotopically light or heavy valine for treatment of control or treated proteome,
  • proteomes were precipitated by centrifugation at 6500 x g, washed in ice-cold methanol, combined in a 1 : 1 control/treated ratio, washed again, then denatured and resolubilized by heating in 1.2% SDS/PBS to 80°C for 5 minutes. Insoluble components were precipitated by centrifugation at 6500 x g and soluble proteome was diluted in 5 ml 0.2% SDS/PBS. Labeled proteins were bound to avidin-agarose beads (170 ⁇ resuspended beads/sample, Thermo Pierce) while rotating overnight at 4°C.
  • Bead-linked proteins were enriched by washing three times each in PBS and water, then resuspended in 6 M urea/PBS (Sigma) and reduced in TCEP (1 mM, Sigma), alkylated with iodoacetamide (18 mM, Sigma), then washed and resuspended in 2 M urea and trypsinized overnight with 0.5 mg/ml sequencing grade trypsin (Promega). Tryptic peptides were eluted off.
  • TEV buffer solution water, TEV buffer, 100 mM dithiothreitol
  • Peptides were diluted in water and acidified with formic acid (1.2 M, Spectrum) and prepared for analysis.
  • Samples were analyzed using an Q Exactive Plus mass spectrometer (Thermo Fisher Scientific) using a 5-step Multidimensional Protein Identification Technology (MudPIT) program, using 0 %, 25 %, 50 %, 80 %, and 100 % salt bumps of 500 mM aqueous ammonium acetate and using a gradient of 5-55 % buffer B in buffer A (buffer A: 95:5 water: acetonitrile, 0.1 % formic acid; buffer B 80:20 acetonitrile:water, 0.1 % formic acid). Data was collected in data-dependent acquisition mode with dynamic exclusion enabled (60 s).
  • MSI MSI scan
  • ITMS MS2 scans
  • ProLuCID search methodology in IP2 v.3 (Integrated Proteomics Applications, Inc) (40). Cysteine residues were searched with a static modification for carboxyaminomethylation (+57.02146) and up to two differential modifications for methionine oxidation and either the light or heavy TEV tags (+464.28596 or +470.29977, respectively). Peptides were required to have at least one tryptic end and to contain the TEV modification. ProLUCID data was filtered through DTASelect to achieve a peptide false-positive rate below 1%.
  • Gel-Based ABPP Gel-Based ABPP methods were performed as previously described (41). Recombinant PTGR1 (0.1 ⁇ g) protein (Origene) was pre-treated with DMSO or Licochalcone A, respectively, for 1 h at 37°C in an incubation volume of 50 mL PBS, and were subsequently treated with IAyne (1 mM final concentration) for 30 min at 37°C.
  • CuAAC was performed to append rhodamine-azide onto IAyne probe-labeled proteins.
  • the samples were separated by SDS/PAGE and scanned using a ChemiDoc MP (Bio-Rad Laboratories, Inc). Inhibition of target labeling was assessed by densitometry using
  • Metabolomic profiling was performed as previously reported (39,42). For metabolomic profiling, 2 million cells were seeded in complete media and allowed to adhere overnight. They were then washed with PBS and refed with serum -free media containing 10 ⁇ of compound in DMSO or DMSO vehicle control at 0.1% DMSO final concentration for 6 hours. The cells were harvested, flash-frozen, and metabolomes were extracted in 3 mL of 2: 1 chloroform:methanol and 1 mL of PBS with inclusion of internal standards dodecyl glycerol (10 nmol, Santa Cruz Biotechnology) and pentadecanoic acid (10 nmol, Sigma-Aldrich).
  • Solvent modifiers 0.1 % formic acid with 5 mM ammonium formate and 0.1 % ammonium hydroxide were used to assist ion formation as well as to improve the LC resolution in both positive and negative ionization modes, respectively.
  • the flow rate for each run started at 0.1 ml/min for 5 min to alleviate backpressure associated with injecting chloroform.
  • the gradient started at 0 % B and increased linearly to 100 % B over the course of 45 min with a flow rate of 0.4 ml/min, followed by an isocratic gradient of 100 % B for 17 min at 0.5 ml/min before equilibrating for 8 min at 0 % B with a flow rate of 0.5 ml/min.
  • MS analysis was performed with an electrospray ionization (ESI) source on an Agilent 6430 QQQ LC -MS/MS (Agilent Technologies).
  • the capillary voltage was set to 3.0 kV, and the fragmentor voltage was set to 100 V.
  • the drying gas temperature was 350°C, the drying gas flow rate was 10 1/min, and the nebulizer pressure was 35 psi.
  • Metabolites were identified by SRM of the transition from precursor to product ions at associated optimized collision energies and retention times as previously described (39,42). Metabolites were quantified by integrating the area under the curve, and then normalized to internal standard values. Metabolite levels are expressed as relative abundances as compared to controls.
  • PTGR1 Knockdown Targets were knocked down stably with shRNA as previously described (39,42).
  • shControl targeting GFP
  • shPTGRl constructs Sigma
  • lipofectamine 2000 Thermo Fisher Scientific
  • Lentivirus was collected from filtered cultured medium 48 h post-transfection and used to infect the target cancer cell line with Polybrene (0.01 mg/ml).
  • Target cells were selected over 3 days with 1 mg/mL puromycin.
  • the short hairpin sequences for the generation of PTGR1 knockdown lines were:
  • qPCR qPCR was performed using the manufacturer's protocol for Fisher Maxima SYBR Green with 10 ⁇ primer concentrations. Primer sequences for Fisher Maxima SYBR Green were derived from Harvard Primer Bank. Primer sequences are as follows:
  • PTGR1 forward AGCACTTTGTTGGCTATCCTAC (SEQ ID NO:6)
  • PTGR1 reverse CCCCATCATTGTATCACCTTCC (SEQ ID NO:7)
  • Cyclophilin forward CCCACCGTGTTCTTCGACATT (SEQ ID NO:8)
  • Cyclophilin reverse GGACCCGTATGCTTTAGGATGA (SEQ ID NO:9).
  • lOx port injection solutions in Seahorse respiration buffer all pH adjusted to 7.4, were prepared as follows (final concentrations in parentheses): port A - 10 ⁇ oligomycin (1 ⁇ final); port B - 1 mM palmitoyl carnitine (100 ⁇ final) or 100 ⁇ WP1130 (10 ⁇ final); port C - 3 ⁇ FCCP (0.3 ⁇ final); port D - 5 ⁇ rotenone and 5 ⁇ antimycin A (0.5 ⁇ final).
  • the Seahorse program ran as follows: basal measurement, 3 cycles; inject port A (oligomycin), 3 cycles; inject port B (compounds), 3 cycles; inject port C (FCCP), 3 cycles; inject port D (rotenone and antimycin A), 3 cycles. Each cycles consisted of mix for 3 min, wait for 2 min, measure for 3 min.
  • HMN-214 a novel oral polo-like kinase inhibitor, in patients with advanced solid tumors.
  • Methods Mol. Biol. Clifton NJ 1238, 487-509 (15) Xiao, Z., Zhang, P., and Ma, L. (2016) The role of deubiquitinases in breast cancer.
  • Licochalcone A induces autophagy through PI3K/Akt/mTOR inactivation and autophagy suppression enhances Licochalcone A-induced apoptosis of human cervical cancer cells.
  • Tandem orthogonal proteolysis- activity-based protein profiling (TOP-ABPP)— a general method for mapping sites of probe modification in proteomes. Nat. Protoc. 2, 1414-1425; (39) Louie, S. M., Grossman, E. A., Crawford, L. A., Ding, L., Camarda, R., Huffman, T. R., Miyamoto, D. K., Goga, A., Weerapana, E., and Nomura, D. K.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des compositions utiles pour inhiber l'activité de la prostaglandine réductase 1 (PTGR1). L'invention concerne en outre un procédé de traitement du cancer, ce procédé consistant à administrer à un sujet ayant besoin d'un tel traitement une quantité efficace d'un inhibiteur de la PTGR1. Un autre aspect de l'invention concerne un procédé de traitement d'un cancer du sein triple négatif, ce procédé consistant à administrer à un sujet ayant besoin d'un tel traitement une quantité efficace d'un inhibiteur de la PTGR1. Un autre aspect de l'invention concerne une composition pharmaceutique contenant un inhibiteur de la PTGR1 et un excipient pharmaceutiquement acceptable. Dans des modes de réalisation préférés, l'inhibiteur de la PTGR1 est un composé tel que décrit dans la description.
PCT/US2018/017702 2017-02-10 2018-02-09 Compositions pour le traitement du cancer du sein WO2018148598A1 (fr)

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CN113613654A (zh) * 2019-10-15 2021-11-05 大连万春布林医药有限公司 治疗铁紊乱的组合物和方法
CN113613654B (zh) * 2019-10-15 2024-01-26 大连万春布林医药有限公司 普那布林在制备增加非转移性乳腺癌患者触珠蛋白的药物中的用途
CN115466266A (zh) * 2022-02-28 2022-12-13 山东中医药大学 mTOR蛋白降解靶向嵌合体及其制备方法和应用
CN115466266B (zh) * 2022-02-28 2023-11-07 山东中医药大学 mTOR蛋白降解靶向嵌合体及其制备方法和应用

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