WO2020077361A1 - Composés et leurs procédés d'utilisation - Google Patents

Composés et leurs procédés d'utilisation Download PDF

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Publication number
WO2020077361A1
WO2020077361A1 PCT/US2019/056318 US2019056318W WO2020077361A1 WO 2020077361 A1 WO2020077361 A1 WO 2020077361A1 US 2019056318 W US2019056318 W US 2019056318W WO 2020077361 A1 WO2020077361 A1 WO 2020077361A1
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Prior art keywords
optionally substituted
alkyl
compound
heterocyclyl
aryl
Prior art date
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PCT/US2019/056318
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English (en)
Inventor
Anders M. NAAR
Gerhard Wagner
Joy Nishikawa
Su Wu
Sara J. BUHRLAGE
Andras Pal BOESZOERMENYI
Haribabu Arthanari
Christoph GORGULLA
Original Assignee
The General Hospital Corporation
President And Fellows Of Harvard College
Dana-Farber Cancer Institute, Inc.
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Application filed by The General Hospital Corporation, President And Fellows Of Harvard College, Dana-Farber Cancer Institute, Inc. filed Critical The General Hospital Corporation
Publication of WO2020077361A1 publication Critical patent/WO2020077361A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/433—Thidiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
    • C07C235/76—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/738—Esters of keto-carboxylic acids or aldehydo-carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/16—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with acylated ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
    • C07D295/112—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/04—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the invention provides compounds, compositions containing them, and methods of their use.
  • Elevated de novo fatty acid biosynthesis is a hallmark metabolic adaptation in many cancers that supports survival, proliferation, and metastasis under adverse (e.g. anaerobic and nutrient- deficient) conditions.
  • DNFA de novo fatty acid biosynthesis
  • cancer cells progress to hyper-proliferative and ultimately malignant states while exhibiting a series of hallmark traits. Among these is elevated de novo fatty acid biosynthesis (DNFA), the metabolic conversion of carbohydrates into lipids. Because cancer cells prefer DNFA to fuel necessary membrane and energy production, elevated DNFA enzymes often correlate with advanced stage tumors. Most healthy adult cells, even those with high turnover, prefer circulating lipids for cellular needs. In adults, DNFA activity is restricted to tissues such as liver and adipose, predominately for energy storage, and even they can tolerate its inhibition. Fetuses rely on DNFA for rapid cell proliferation and tissue development. Robust DNFA activity is essential for embryonic development and even dietary fat cannot substitute for DNFA. Thus, cancer’s tendency to employ DNFA more closely resembles embryonic than adult cell behavior, which may offer an opportunity to advance the quest for cancer-specific
  • DNFA occurs in a catalytic cascade with the aid of several lipogenic enzymes, including acetyl- CoA carboxylase (ACACA), fatty acid synthase (FASN), and stearoyl-CoA desaturase (SCD).
  • ACACA acetyl- CoA carboxylase
  • FASN fatty acid synthase
  • SCD stearoyl-CoA desaturase
  • the substrate of DNFA acetyl coenzyme A (CoA)
  • ACLY ATP citrate lyase
  • ACSS2 acyl-coenzyme A synthetase
  • SREBP1 Sterol regulatory element-binding protein 1 directly regulates the transcription of DNFA enzymes by binding their gene promoters, and thus serves as the master regulator of cellular lipid production.
  • SREBP1 Insulin and growth factor signaling stimulates SREBP1 activation in cancer through the PI3K/AKT pathway. Activated SREBP1 migrates into the nucleus, binds to sterol regulatory elements (SRE) in the lipogenic gene promoters and further support tumor growth.
  • SRE sterol regulatory elements
  • the specific elements of SREBP1’s mechanisms of action could be regarded as an intriguing array of targets. Particularly in melanoma, room remains to more completely characterize SREBP1’s role in oncogenic signaling for DNFA, and more fully explore its potential clinical relevance for cancer prognosis and treatment.
  • the invention provides compounds.
  • the compound is a compound of formula (I):
  • n 1 , 2, 3, 4, or 5;
  • each R 1 is independently optionally substituted C3-10 cycloalkyl, optionally substituted C1-6 alkyl, optionally substituted C1 -9 heterocyclyl, halogen, optionally substituted C1 -6 alkoxy, optionally substituted C2-6 alkenyloxy, optionally substituted C2-6 alkynyloxy, or optionally substituted Ce-io aryloxy; and
  • R 2 is hydroxyl, optionally substituted C1 -6 alkoxy, or -N(R 3 )2, wherein each R 3 is independently H, optionally substituted C1 -6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted cycloalkyl, optionally substituted Ce-io aryl C1 -6 alkyl, or optionally substituted C1-9 heterocyclyl C1 -6 alkyl, or both R 3 , together with the atom to which they are attached, combine to form an optionally substituted C1 -9 heterocyclyl.
  • the compound of formula (I) is not any one of the following compounds:
  • n is 1 .
  • the compound of formula (I) is a compound of formula (IB):
  • R 2 is -N(R 3 )2. In certain embodiments, R 2 is a group of formula:
  • X is CH or N
  • R 4 is H, optionally substituted C1-6 alkyl, optionally substituted cycloalkyl, optionally substituted C6-10 aryl, or optionally substituted C1 -9 heteroaryl.
  • X is CH. In other embodiments, X is N.
  • R 4 is optionally substituted Ce-io aryl, optionally substituted C1 -6 alkyl, or optionally substituted cycloalkyl. In yet further embodiments, R 4 is methyl or trifluoromethyl. In still further embodiments, R 4 is
  • each R 3 is independently H or optionally substituted C1 -9 heterocyclyl C1-6 alkyl.
  • R 2 is a group of formula:
  • one of X 1 and X 2 is CH2, and the remaining X 1 or X 2 is NR 5 or O, wherein R 5 is H, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted Ce-io aryl, or optionally substituted Ce-io aryl C1 -6 alkyl.
  • X 1 is CH2. In yet further embodiments, X 2 is CH2. In still further embodiments, the remaining X 1 or X 2 is O. In other embodiments, the remaining X 1 or X 2 is NR 5 .
  • R 5 is H, optionally substituted C1 -6 alkyl, optionally substituted C2-6 alkynyl, or optionally substituted Ce-io aryl C1-6 alkyl.
  • R 1 is optionally substituted cycloalkyl, optionally substituted C1-9 heterocyclyl, or optionally substituted C2-6 alkynyloxy.
  • R 1 is optionally substituted cycloalkyl.
  • R 1 is optionally substituted cyclohexyl.
  • the compound is selected from the group consisting of: PCT/US2019/056318
  • the compound is a compound of formula (II):
  • n 0, 1 , or 2;
  • Z is -SO2- or -S-;
  • R 1 is -COOR A or -CONR B R c ;
  • each R 2 when present, is independently halogen
  • R 3 is optionally substituted Ce-io aryl C1 -6 alkyl or optionally substituted C1 -6 alkyl;
  • R A is H or optionally substituted C1 -6 alkyl
  • R B is optionally substituted Ce-io aryl, optionally substituted Ce-io aryl C1-6 alkyl, optionally substituted 5-membered heteroaryl, optionally substituted bicyclic heteroaryl, optionally substituted C1-9 heterocyclyl, or optionally substituted C1 -9 heterocyclyl C1-6 alkyl; and R c is H or optionally substituted C1-6 alkyl; or R B and R c combine to form an optionally substituted C1 -9 heterocyclyl.
  • the compound of formula (II) is not a compound of any one of the following structures:
  • n 1 .
  • Z is -SO2-.
  • the compound of formula (II) is a compound of formula (II A) :
  • R 3 is -(CH2)-R D , wherein R D is optionally substituted phenyl.
  • R D is phenyl substituted at the para position with halogen or C1 -6 alkoxy.
  • R 1 is -CONR B R c .
  • R B is optionally substituted Ce-io aryl.
  • R B is optionally substituted 6-membered heteroaryl.
  • R c is H.
  • R 2 is bromo. In further embodiments, R 2 is chloro.
  • the invention provides pharmaceutical compositions.
  • the pharmaceutical composition comprises a pharmaceutically acceptable excipient and a compound of formula (I):
  • n 1 , 2, 3, 4, or 5;
  • each R 1 is independently optionally substituted cycloalkyl, optionally substituted C1 -6 alkyl, optionally substituted C1 -9 heterocyclyl, halogen, optionally substituted C1 -6 alkoxy, optionally substituted C2-6 alkenyloxy, optionally substituted C2-6 alkynyloxy, or optionally substituted Ce-io aryloxy; and
  • R 2 is hydroxyl, optionally substituted C1 -6 alkoxy, or -N(R 3 )2, wherein each R 3 is independently H, optionally substituted C1 -6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted cycloalkyl, optionally substituted Ce-io aryl C1 -6 alkyl, or optionally substituted C1-9 heterocyclyl C1 -6 alkyl, or both R 3 , together with the atom to which they are attached, combine to form an optionally substituted C1 -9 heterocyclyl.
  • n is 1 .
  • the compound of formula (I) is a compound of formula (IA):
  • the compound of formula (I) is a compound of formula (IB):
  • R 2 is -N(R 3 )2. In yet further embodiments, R 2 is a group of formula:
  • X is CH or N
  • R 4 is H, optionally substituted C1-6 alkyl, optionally substituted cycloalkyl, optionally substituted Ce- io aryl, or optionally substituted C1-9 heteroaryl.
  • X is CH. In other embodiments, X is N.
  • R 4 is optionally substituted C6-10 aryl, optionally substituted C1-6 alkyl, or optionally substituted cycloalkyl. In particular embodiments, R 4 is methyl or trifluoromethyl. In some embodiments, R 4 is
  • each R 3 is independently H or optionally substituted C1-9 heterocyclyl C1 -6 alkyl.
  • R 2 is a group of formula:
  • one of X 1 and X 2 is CH2, and the remaining X 1 or X 2 is NR 5 or O, wherein R 5 is H, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted Ce-io aryl, or optionally substituted Ce-io aryl C1 -6 alkyl.
  • X 1 is CH2.
  • X 2 is CH2.
  • the remaining X 1 or X 2 is O.
  • the remaining X 1 or X 2 is NR 5 .
  • R 5 is H, optionally substituted C1 -6 alkyl, optionally substituted C2-6 alkynyl, or optionally substituted Ce-io aryl C1 -6 alkyl.
  • R 1 is optionally substituted cycloalkyl, optionally substituted C1-9 heterocyclyl, or optionally substituted C2-6 alkynyloxy.
  • R 1 is optionally substituted cycloalkyl.
  • R 1 is optionally substituted cyclohexyl.
  • the compound is a compound of any aspect.
  • the pharmaceutical composition comprises a pharmaceutically acceptable excipient and a compound of formula (II) :
  • n 0, 1 , or 2;
  • Z is -SO2- or -S-;
  • R 1 is -COOR A or -CONR B R c ;
  • each R 2 when present, is independently halogen
  • R 3 is optionally substituted Ce-io aryl C1 -6 alkyl or optionally substituted C1 -6 alkyl;
  • R A is H or optionally substituted C1 -6 alkyl
  • R A is H or optionally substituted C1 -6 alkyl
  • R B is optionally substituted Ce-io aryl, optionally substituted Ce-io aryl C1-6 alkyl, optionally substituted 5-membered heteroaryl, optionally substituted bicyclic heteroaryl, optionally substituted C1-9 heterocyclyl, or optionally substituted C1 -9 heterocyclyl C1-6 alkyl; and R c is H or optionally substituted C1-6 alkyl; or R B and R c combine to form an optionally substituted C1 -9 heterocyclyl.
  • n 1 .
  • Z is -SO2-.
  • the compound of formula (II) is a compound of formula (II A) :
  • R 3 is -(CH2)-R D , wherein R D is optionally substituted phenyl.
  • R D is phenyl substituted at the para position with halogen or C1 -6 alkoxy.
  • R 1 is -CONR B R c .
  • R B is optionally substituted C6-10 aryl.
  • R B is optionally substituted 6-membered heteroaryl.
  • R c is H.
  • R 2 is halogen (e.g., R 2 is chloro).
  • the compound is a compound of any aspect.
  • the invention provides a method of treating cancer in a subject by administering to the subject in need thereof a therapeutically effective amount of the compound of the invention or the pharmaceutical composition of the invention.
  • the compound is a compound of formula (I):
  • n 1 , 2, 3, 4, or 5;
  • each R 1 is independently optionally substituted cycloalkyl, optionally substituted C1 -6 alkyl, optionally substituted C1 -9 heterocyclyl, halogen, optionally substituted C1 -6 alkoxy, optionally substituted C2-6 alkenyloxy, optionally substituted C2-6 alkynyloxy, or optionally substituted Ce-io aryloxy; and
  • R 2 is hydroxyl, optionally substituted C1 -6 alkoxy, or -N(R 3 )2, wherein each R 3 is independently H, optionally substituted C1 -6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted cycloalkyl, optionally substituted Ce-io aryl C1 -6 alkyl, or optionally substituted C1-9 heterocyclyl C1 -6 alkyl, or both R 3 , together with the atom to which they are attached, combine to form an optionally substituted C1 -9 heterocyclyl.
  • the compound is a compound of formula (II):
  • n 0, 1 , or 2;
  • Z is -SO2- or -S-;
  • R 1 is -COOR A or -CONR B R c ;
  • each R 2 when present, is independently halogen
  • R 3 is optionally substituted Ce-io aryl C1 -6 alkyl or optionally substituted C1 -6 alkyl;
  • R A is H or optionally substituted C1 -6 alkyl
  • R B is optionally substituted Ce-io aryl, optionally substituted Ce-io aryl C1-6 alkyl, optionally substituted 5-membered heteroaryl, optionally substituted bicyclic heteroaryl, optionally substituted C1-9 heterocyclyl, or optionally substituted C1 -9 heterocyclyl C1-6 alkyl; and R c is H or optionally substituted C1-6 alkyl; or R B and R c combine to form an optionally substituted C1 -9 heterocyclyl.
  • the cancer is melanoma, glioblastoma, glioma, prostate cancer, breast cancer, non-small cell lung cancer, or kidney cancer (e.g., clear cell renal cell carcinoma).
  • the cancer is metastatic.
  • the invention provides a method of treating a metabolic disorder in a subject by administering to the subject in need thereof a therapeutically effective amount of the compound of the invention or the pharmaceutical composition of the invention.
  • the compound is a compound of formula (I):
  • n 1 , 2, 3, 4, or 5;
  • each R 1 is independently optionally substituted cycloalkyl, optionally substituted C1 -6 alkyl, optionally substituted C1 -9 heterocyclyl, halogen, optionally substituted C1 -6 alkoxy, optionally substituted C2-6 alkenyloxy, optionally substituted C2-6 alkynyloxy, or optionally substituted Ce-io aryloxy; and
  • R 2 is hydroxyl, optionally substituted C1 -6 alkoxy, or -N(R 3 )2, wherein each R 3 is independently H, optionally substituted C1 -6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted cycloalkyl, optionally substituted Ce-io aryl C1 -6 alkyl, or optionally substituted C1-9 heterocyclyl C1 -6 alkyl, or both R 3 , together with the atom to which they are attached, combine to form an optionally substituted C1 -9 heterocyclyl.
  • the compound is a compound of formula (II):
  • n 0, 1 , or 2;
  • Z is -SO2- or -S-;
  • R 1 is -COOR A or -CONR B R c ;
  • each R 2 when present, is independently halogen
  • R 3 is optionally substituted Ce-io aryl C1 -6 alkyl or optionally substituted C1 -6 alkyl;
  • R A is H or optionally substituted C1 -6 alkyl
  • R B is optionally substituted Ce-io aryl, optionally substituted Ce-io aryl C1-6 alkyl, optionally substituted 5-membered heteroaryl, optionally substituted bicyclic heteroaryl, optionally substituted C1-9 heterocyclyl, or optionally substituted C1 -9 heterocyclyl C1-6 alkyl; and R c is H or optionally substituted C1-6 alkyl; or R B and R c combine to form an optionally substituted C1 -9 heterocyclyl.
  • the metabolic disorder is nonalcoholic steatohepatitis or cardiovascular disease.
  • the invention provides a method of inhibiting binding between SREBP1 and the KIX domain of MED15 or CBP in a subject in need thereof by administering to the subject an effective amount of the compound of the invention or the pharmaceutical composition of the invention.
  • the compound is a compound of formula (I):
  • n 1 , 2, 3, 4, or 5;
  • each R 1 is independently optionally substituted cycloalkyl, optionally substituted C1 -6 alkyl, optionally substituted C1 -9 heterocyclyl, halogen, optionally substituted C1 -6 alkoxy, optionally substituted C2-6 alkenyloxy, optionally substituted C2-6 alkynyloxy, or optionally substituted Ce-io aryloxy; and
  • R 2 is hydroxyl, optionally substituted C1 -6 alkoxy, or -N(R 3 )2, wherein each R 3 is independently H, optionally substituted C1 -6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted cycloalkyl, optionally substituted Ce-io aryl C1 -6 alkyl, or optionally substituted C1-9 heterocyclyl C1 -6 alkyl, or both R 3 , together with the atom to which they are attached, combine to form an optionally substituted C1 -9 heterocyclyl.
  • the compound is a compound of formula (II):
  • n 0, 1 , or 2;
  • Z is -SO2- or -S-;
  • R 1 is -COOR A or -CONR B R c ;
  • each R 2 when present, is independently halogen
  • R 3 is optionally substituted Ce-io aryl C1 -6 alkyl or optionally substituted C1 -6 alkyl;
  • R A is H or optionally substituted C1 -6 alkyl
  • R B is optionally substituted Ce-io aryl, optionally substituted Ce-io aryl C1-6 alkyl, optionally substituted 5-membered heteroaryl, optionally substituted bicyclic heteroaryl, optionally substituted C1-9 heterocyclyl, or optionally substituted C1 -9 heterocyclyl C1-6 alkyl; and R c is H or optionally substituted C1-6 alkyl; or R B and R c combine to form an optionally substituted C1 -9 heterocyclyl.
  • the compound or the pharmaceutical composition is administered enterally (e.g., orally).
  • the compound or the pharmaceutical composition is administered parenterally (e.g., intramuscularly, intratumorally, intravenously, subcutaneously, buccally, sublingually, sublabially, by inhalation, intra-arterially, intraventricularly, intraspinally, intrathecally, intraorbitally, intracranially, or topically).
  • the subject is a human.
  • the method further includes administering a fatty acid/cholesterol homeostatsis modulator. In certain embodiments, the method further includes administering an inducer of ferroptotic cell death. In particular embodiments, the method further includes administering 666-1 5, fatostatin, A-485, PF429242, erastin, or a pharmaceutically acceptable salt thereof.
  • the invention provides a method of killing a cancer cell by contacting the cancer cell with the compound of the invention.
  • the compound is a compound of formula (I):
  • n 1 , 2, 3, 4, or 5;
  • each R 1 is independently optionally substituted cycloalkyl, optionally substituted C1 -6 alkyl, optionally substituted C1 -9 heterocyclyl, halogen, optionally substituted C1 -6 alkoxy, optionally substituted C2-6 alkenyloxy, optionally substituted C2-6 alkynyloxy, or optionally substituted Ce-io aryloxy; and
  • R 2 is hydroxyl, optionally substituted C1 -6 alkoxy, or -N(R 3 )2, wherein each R 3 is independently H, optionally substituted C1 -6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted cycloalkyl, optionally substituted Ce-io aryl C1 -6 alkyl, or optionally substituted C1-9 heterocyclyl C1 -6 alkyl, or both R 3 , together with the atom to which they are attached, combine to form an optionally substituted C1 -9 heterocyclyl.
  • the compound is a compound of formula (II):
  • n 0, 1 , or 2;
  • Z is -SO2- or -S-;
  • R 1 is -COOR A or -CONR B R c ;
  • each R 2 when present, is independently halogen
  • R 3 is optionally substituted Ce-io aryl C1 -6 alkyl or optionally substituted C1 -6 alkyl;
  • R A is H or optionally substituted C1 -6 alkyl
  • R B is optionally substituted Ce-io aryl, optionally substituted Ce-io aryl C1-6 alkyl, optionally substituted 5-membered heteroaryl, optionally substituted bicyclic heteroaryl, optionally substituted C1-9 heterocyclyl, or optionally substituted C1 -9 heterocyclyl C1-6 alkyl; and R c is H or optionally substituted C1-6 alkyl; or R B and R c combine to form an optionally substituted C1 -9 heterocyclyl.
  • the cancer cell is a melanoma cell, glioblastoma cell, prostate cancer cell, non-small cell lung cancer cell, or kidney cancer cell.
  • the cell is in a subject.
  • the subject is human.
  • the method further includes contacting the cancer cell with a fatty acid/cholesterol homeostatsis modulator.
  • the method further includes contacting the cancer cell with an inducer of ferroptotic cell death.
  • the method further includes contacting the cancer cell with 666-15, fatostatin, A-485, PF429242, or erastin.
  • the invention provides an agent capable of binding the KIX domain of CBP or MED15 to inhibit the binding between SREBP1 and the KIX domain of MED15 or CBP.
  • the agent is not a compound of any one of the following structures:
  • the agent is a small molecule (e.g., the small molecule is a compound of the invention).
  • the agent is an antigen-binding protein (e.g., an antibody or an antigen-binding fragment thereof).
  • the invention provides a method of inhibiting binding between SREBP1 and the KIX domain of MED15 or CBP by contacting MED15 or CBP with the agent of the invention.
  • MED15 is in a cell.
  • CBP is in a cell.
  • the cell is in a subject in need of inhibition of the binding between SREBP1 and the KIX domain of MED15 or CBP.
  • the subject suffers from a cancer.
  • the cancer is melanoma, glioblastoma, glioma, prostate cancer, breast cancer, non-small cell lung cancer, or kidney cancer.
  • the subject suffers from a metabolic disorder.
  • the metabolic disorder is nonalcoholic steatohepatitis or a cardiovascular disease.
  • the present disclosure also includes the following enumerated items
  • n 1 , 2, 3, 4, or 5;
  • each R 1 is independently optionally substituted C3-10 cycloalkyl, optionally substituted C1-6 alkyl, optionally substituted C1 -9 heterocyclyl, halogen, optionally substituted C1 -6 alkoxy, optionally substituted C2-6 alkenyloxy, optionally substituted C2-6 alkynyloxy, or optionally substituted Ce-io aryloxy; and
  • R 2 is hydroxyl, optionally substituted C1 -6 alkoxy, or -N(R 3 )2, wherein each R 3 is independently H, optionally substituted C1 -6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted cycloalkyl, optionally substituted Ce-io aryl C1 -6 alkyl, or optionally substituted C1-9 heterocyclyl C1 -6 alkyl, or both R 3 , together with the atom to which they are attached, combine to form an optionally substituted C1 -9 heterocyclyl;
  • X is CH or N
  • R 4 is H, optionally substituted C1-6 alkyl, optionally substituted cycloalkyl, optionally substituted Ce- io aryl, or optionally substituted C1-9 heteroaryl.
  • R 4 is optionally substituted C6-10 aryl, optionally substituted C1 -6 alkyl, or optionally substituted cycloalkyl.
  • one of X 1 and X 2 is CH2, and the remaining X 1 or X 2 is NR 5 or O, wherein R 5 is H, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted Ce-io aryl, or optionally substituted Ce-io aryl C1 -6 alkyl.
  • R 5 is H, optionally substituted C1 -6 alkyl, optionally substituted C2-6 alkynyl, or optionally substituted Ce-io aryl C1-6 alkyl.
  • R 1 is optionally substituted cycloalkyl, optionally substituted C1 -9 heterocyclyl, or optionally substituted C2-6 alkynyloxy.
  • n 0, 1 , or 2;
  • Z is -SO2- or -S-;
  • R 1 is -COOR A or -CONR B R c ;
  • each R 2 when present, is independently halogen
  • R 3 is optionally substituted Ob-io aryl C1 -6 alkyl or optionally substituted C1 -6 alkyl;
  • R A is H or optionally substituted C1-6 alkyl
  • R B is optionally substituted Ob-io aryl, optionally substituted Ce-io aryl C1-6 alkyl, optionally substituted 5-membered heteroaryl, optionally substituted bicyclic heteroaryl, optionally substituted C1-9 heterocyclyl, or optionally substituted C1-9 heterocyclyl C1-6 alkyl; and R c is H or optionally substituted C1-6 alkyl; or R B and R c combine to form an optionally substituted C1-9 heterocyclyl ;
  • the compound is not a compound of any one of the following structures:
  • a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula (I):
  • n 1 , 2, 3, 4, or 5;
  • each R 1 is independently optionally substituted cycloalkyl, optionally substituted C1 -6 alkyl, optionally substituted C1 -9 heterocyclyl, halogen, optionally substituted C1 -6 alkoxy, optionally substituted C2-6 alkenyloxy, optionally substituted C2-6 alkynyloxy, or optionally substituted Ce-io aryloxy; and
  • R 2 is hydroxyl, optionally substituted C1 -6 alkoxy, or -N(R 3 )2, wherein each R 3 is independently H, optionally substituted C1 -6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted cycloalkyl, optionally substituted Ce-io aryl C1 -6 alkyl, or optionally substituted C1-9 heterocyclyl C1 -6 alkyl, or both R 3 , together with the atom to which they are attached, combine to form an optionally substituted C1 -9 heterocyclyl.
  • X is CH or N
  • R 4 is H, optionally substituted C1-6 alkyl, optionally substituted cycloalkyl, optionally substituted Ce- io aryl, or optionally substituted C1-9 heteroaryl.
  • each R 3 is independently H or optionally substituted C1-9 heterocyclyl C1-6 alkyl.
  • one of X 1 and X 2 is CH2, and the remaining X 1 or X 2 is NR 5 or O, wherein R 5 is H, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted Ce-io aryl, or optionally substituted Ce-io aryl C1 -6 alkyl.
  • R 5 is H, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkynyl, or optionally substituted Ce-io aryl C1 -6 alkyl.
  • composition of item 37, wherein the compound is a compound of any one of items 1 to 24.
  • a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula (II):
  • n 0, 1 , or 2;
  • Z is -SO2- or -S-;
  • R 1 is -COOR A or -CONR B R c ;
  • each R 2 when present, is independently halogen
  • R 3 is optionally substituted Ce-io aryl C1 -6 alkyl or optionally substituted C1 -6 alkyl;
  • R A is H or optionally substituted C1 -6 alkyl
  • R A is H or optionally substituted C1 -6 alkyl
  • R B is optionally substituted Ce-io aryl, optionally substituted Ce-io aryl C1-6 alkyl, optionally substituted 5-membered heteroaryl, optionally substituted bicyclic heteroaryl, optionally substituted C1-9 heterocyclyl, or optionally substituted C1 -9 heterocyclyl C1-6 alkyl; and R c is H or optionally substituted C1-6 alkyl; or R B and R c combine to form an optionally substituted C1 -9 heterocyclyl.
  • a method of treating cancer in a subject comprising administering to the subject in need thereof a therapeutically effective amount of the compound of any one of items 1 to 36, the pharmaceutical composition of any one of items 37 to 72, the compound of formula (I), or the compound of formula (II); wherein the compound of formula (I) has the following structure:
  • n 1 , 2, 3, 4, or 5;
  • each R 1 is independently optionally substituted cycloalkyl, optionally substituted C1 -6 alkyl, optionally substituted C1 -9 heterocyclyl, halogen, optionally substituted C1 -6 alkoxy, optionally substituted C2-6 alkenyloxy, optionally substituted C2-6 alkynyloxy, or optionally substituted Ce-io aryloxy; and
  • R 2 is hydroxyl, optionally substituted C1 -6 alkoxy, or -N(R 3 )2, wherein each R 3 is independently H, optionally substituted C1 -6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted cycloalkyl, optionally substituted Ce-io aryl C1 -6 alkyl, or optionally substituted C1-9 heterocyclyl C1 -6 alkyl, or both R 3 , together with the atom to which they are attached, combine to form an optionally substituted C1 -9 heterocyclyl; and
  • n 0, 1 , or 2;
  • Z is -SO2- or -S-;
  • R 1 is -COOR A or -CONR B R c ;
  • each R 2 when present, is independently halogen;
  • R 3 is optionally substituted Ce-io aryl C1 -6 alkyl or optionally substituted C1 -6 alkyl;
  • R A is H or optionally substituted C1 -6 alkyl
  • R B is optionally substituted Ce-io aryl, optionally substituted Ce-io aryl C1-6 alkyl, optionally substituted 5-membered heteroaryl, optionally substituted bicyclic heteroaryl, optionally substituted C1-9 heterocyclyl, or optionally substituted C1 -9 heterocyclyl C1-6 alkyl; and R c is H or optionally substituted C1-6 alkyl; or R B and R c combine to form an optionally substituted C1 -9 heterocyclyl.
  • the cancer is melanoma, glioblastoma, glioma, prostate cancer, breast cancer, non-small cell lung cancer, or kidney cancer.
  • a method of treating a metabolic disorder in a subject comprising administering to the subject in need thereof a therapeutically effective amount of the compound of any one of items 1 to 36, the pharmaceutical composition of any one of items 37 to 72, a compound of formula (I), or a compound of formula (II);
  • n 1 , 2, 3, 4, or 5;
  • each R 1 is independently optionally substituted cycloalkyl, optionally substituted C1 -6 alkyl, optionally substituted C1 -9 heterocyclyl, halogen, optionally substituted C1 -6 alkoxy, optionally substituted C2-6 alkenyloxy, optionally substituted C2-6 alkynyloxy, or optionally substituted Ce-io aryloxy; and
  • R 2 is hydroxyl, optionally substituted C1 -6 alkoxy, or -N(R 3 )2, wherein each R 3 is independently H, optionally substituted C1 -6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted cycloalkyl, optionally substituted Ce-io aryl C1 -6 alkyl, or optionally substituted C1-9 heterocyclyl C1 -6 alkyl, or both R 3 , together with the atom to which they are attached, combine to form an optionally substituted C1 -9 heterocyclyl; and
  • n 0, 1 , or 2;
  • Z is -SO2- or -S-;
  • R 1 is -COOR A or -CONR B R c ;
  • each R 2 when present, is independently halogen
  • R 3 is optionally substituted Ce-io aryl C1 -6 alkyl or optionally substituted C1 -6 alkyl;
  • R A is H or optionally substituted C1 -6 alkyl
  • R B is optionally substituted Ce-io aryl, optionally substituted Ce-io aryl C1-6 alkyl, optionally substituted 5-membered heteroaryl, optionally substituted bicyclic heteroaryl, optionally substituted C1-9 heterocyclyl, or optionally substituted C1 -9 heterocyclyl C1-6 alkyl; and R c is H or optionally substituted C1-6 alkyl; or R B and R c combine to form an optionally substituted C1 -9 heterocyclyl.
  • a method of inhibiting binding between SREBP1 and the KIX domain of MED15 or CBP in a subject in need thereof comprising administering to the subject an effective amount of the compound of any one of items 1 to 36, the pharmaceutical composition of any one of items 37 to 72, a compound of formula (I), or a compound of formula (II);
  • n 1 , 2, 3, 4, or 5;
  • each R 1 is independently optionally substituted cycloalkyl, optionally substituted C1 -6 alkyl, optionally substituted C1 -9 heterocyclyl, halogen, optionally substituted C1 -6 alkoxy, optionally substituted C2-6 alkenyloxy, optionally substituted C2-6 alkynyloxy, or optionally substituted Ce-io aryloxy; and
  • R 2 is hydroxyl, optionally substituted C1 -6 alkoxy, or -N(R 3 )2, wherein each R 3 is independently H, optionally substituted C1 -6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted cycloalkyl, optionally substituted Ce-io aryl C1 -6 alkyl, or optionally substituted C1-9 heterocyclyl C1 -6 alkyl, or both R 3 , together with the atom to which they are attached, combine to form an optionally substituted C1 -9 heterocyclyl; and
  • n 0, 1 , or 2;
  • Z is -SO2- or -S-;
  • R 1 is -COOR A or -CONR B R c ;
  • each R 2 when present, is independently halogen
  • R 3 is optionally substituted Ce-io aryl C1 -6 alkyl or optionally substituted C1 -6 alkyl;
  • R A is H or optionally substituted C1 -6 alkyl
  • R B is optionally substituted Ce-io aryl, optionally substituted Ce-io aryl C1-6 alkyl, optionally substituted 5-membered heteroaryl, optionally substituted bicyclic heteroaryl, optionally substituted C1-9 heterocyclyl, or optionally substituted C1 -9 heterocyclyl C1-6 alkyl; and R c is H or optionally substituted C1-6 alkyl; or R B and R c combine to form an optionally substituted C1 -9 heterocyclyl.
  • a method of killing a cancer cell comprising contacting the cancer cell with the compound of any one of items 1 to 36, a compound of formula (I), or a compound of formula (II);
  • n 1 , 2, 3, 4, or 5;
  • each R 1 is independently optionally substituted cycloalkyl, optionally substituted C1 -6 alkyl, optionally substituted C1 -9 heterocyclyl, halogen, optionally substituted C1 -6 alkoxy, optionally substituted C2-6 alkenyloxy, optionally substituted C2-6 alkynyloxy, or optionally substituted Ce-io aryloxy; and
  • R 2 is hydroxyl, optionally substituted C1 -6 alkoxy, or -N(R 3 )2, wherein each R 3 is independently H, optionally substituted C1 -6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted cycloalkyl, optionally substituted Ce-io aryl C1 -6 alkyl, or optionally substituted C1-9 heterocyclyl C1 -6 alkyl, or both R 3 , together with the atom to which they are attached, combine to form an optionally substituted C1 -9 heterocyclyl; and
  • n 0, 1 , or 2;
  • Z is -SO2- or -S-;
  • R 1 is -COOR A or -CONR B R c ;
  • each R 2 when present, is independently halogen
  • R 3 is optionally substituted Ce-io aryl C1 -6 alkyl or optionally substituted C1 -6 alkyl;
  • R A is H or optionally substituted C1 -6 alkyl
  • R B is optionally substituted Ce-io aryl, optionally substituted Ce-io aryl C1-6 alkyl, optionally substituted 5-membered heteroaryl, optionally substituted bicyclic heteroaryl, optionally substituted C1-9 heterocyclyl, or optionally substituted C1 -9 heterocyclyl C1-6 alkyl; and R c is H or optionally substituted C1-6 alkyl; or R B and R c combine to form an optionally substituted C1 -9 heterocyclyl.
  • cancer cell is a melanoma cell, glioblastoma cell, prostate cancer cell, non-small cell lung cancer cell, or kidney cancer cell.
  • agent of item 95 The agent of item 94, wherein the agent is a small molecule.
  • agent of item 95 wherein the agent is the compound of any one of items 1 to 36.
  • agent of item 94 wherein the agent is an antigen-binding protein.
  • antigen-binding protein is an antibody or an antigen-binding fragment thereof.
  • a method of inhibiting binding between SREBP1 and the KIX domain of MED15 or CBP comprising contacting MED1 5 or CBP with the agent of any one of items 94 to 98.
  • MED15 or CBP is in a cell.
  • 101 The method of item 100, wherein the cell is in a subject in need of inhibition of the binding between SREBP1 and the KIX domain of MED15 or CBP.
  • the method of item 102, wherein the cancer is melanoma, glioblastoma, glioma, prostate cancer, breast cancer, non-small cell lung cancer, or kidney cancer.
  • acyl represents a monovalent substituent -C(0)-R, where R is alkyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, or heterocyclyl.
  • acyloxy represents a monovalent substituent -OR, where R is acyl.
  • alkenyl represents an acyclic, straight or branched chain, monovalent hydrocarbon group containing one, two, or three carbon-carbon double bonds. Unless otherwise specified, an unsubstituted alkenyl has a carbon count from two to six.
  • Non-limiting examples of the alkenyl groups include ethenyl, prop-1 -enyl, prop-2-enyl, 1 -methylethenyl, but-1 -enyl, but-2-enyl, but-3- enyl, 1 -methylprop-1 -enyl, 2-methylprop-1 -enyl, 1 -methylprop-2-enyl, and the like.
  • An optionally substituted alkenyl is an alkenyl group that is optionally substituted as described herein for alkyl.
  • alkenyloxy represents a chemical substituent of formula -OR, where R is a C2-6 alkenyl group, unless otherwise specified.
  • An optionally substituted alkenyloxy is an alkenyloxy group that is optionally substituted as described herein for alkyl.
  • alkoxy represents a chemical substituent of formula -OR, where R is a C1 -6 alkyl group, unless otherwise specified.
  • An optionally substituted alkoxy is an alkoxy group that is optionally substituted as described herein for alkyl.
  • alkoxyaryl represents an aryl substituted with 1 , 2, or 3 groups independently selected from alkoxy.
  • alkyl represents an acyclic, straight or branched chain, saturated hydrocarbon group, which, when unsubstituted, has from one to six carbon atoms, unless otherwise specified.
  • alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec- butyl, iso-butyl, tert-butyl, neopentyl, and the like.
  • Alkyl may be optionally substituted, valency permitting, with one, two, three, four, or five unsubstituted substituents independently selected from the group consisting of: alkoxy; acyloxy; aryloxy; arylalkoxy; cycloalkyl; cycloalkoxy; halogen; heterocyclyl;
  • alkynyl represents an acyclic, straight or branched chain, monovalent hydrocarbon group of from two to six carbon atoms containing one or two carbon-carbon triple bond.
  • alkynyl groups include ethynyl, 1 -propynyl, 2-propynyl, 2-butynyl, and the like.
  • An optionally substituted alkynyl is an alkynyl that is optionally substituted as described herein for alkyl.
  • alkynyloxy represents a chemical substituent of formula -OR, where R is a C2-6 alkynyl group, unless otherwise specified.
  • An optionally substituted alkynyloxy is an alkynyloxy group that is optionally substituted as described herein for alkyl.
  • amino represents a monovalent substituent -NH2 or a divalent substituent -NH-.
  • antibody refers to at least the variable domain of a heavy chain, and normally comprises at least the variable domains of a heavy chain and of a light chain of an
  • Antibodies and antigen-binding fragments include, but are not limited to, polyclonal, monoclonal, multispecific, human, humanized, primatized, or chimeric antibodies, single chain antibodies, epitope-binding fragments, e.g., Fab, Fab' and F(ab')2, Fd, Fvs, single-chain Fvs (scFv), single-chain antibodies, disulfide-linked Fvs (sdFv), fragments comprising either a VL or VH domain, fragments produced by a Fab expression library, and anti-idiotypic (anti-ld) antibodies.
  • Antibody molecules of the invention can be of any type (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgG 1 , lgG2, lgG3, lgG4, lgA1 and lgA2) or subclass of immunoglobulin molecule.
  • aryl represents a monocyclic, bicyclic, or tricyclic carbocyclic ring system having one or two aromatic rings. Unless otherwise specified, unsubstituted aryl groups have a carbon count of six to fourteen (preferably, six to ten). All atoms within an unsubstituted carbocyclic aryl group are carbon atoms.
  • Non-limiting examples of carbocyclic aryl groups include phenyl, naphthyl, 1 ,2- dihydronaphthyl, 1 ,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl, indenyl, etc.
  • aryl may be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of: alkyl; acyl; acyloxy; alkenyl; alkynyl; alkoxy; aryl; aryloxy; aryloyl; arylalkyl; arylalkoxy; cycloalkyl; cycloalkoxy; halogen; haloalkyl; haloalkoxy; heterocyclyl; heteroaryl;
  • heterocyclyloxy heteroaryloxy; heteroaryloxy; hydroxyl; nitro; thiol; cyano; -NR2, where each R is independently hydrogen, alkyl, acyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, or heteroaryl; -SR A ; -COOR A , where R A is hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, or heteroaryl; -CON(R B )2; and -S02N(R B )2, where each R B is independently hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, or heteroaryl.
  • aryl alkenyl represents an alkenyl group substituted with one or two aryl group(s).
  • each of the aryl and alkenyl portions may be independently, optionally substituted as described herein for aryl and alkyl, respectively.
  • aryl alkyl represents an alkyl group substituted with one or two aryl group(s).
  • each of the aryl and alkyl portions may be independently, optionally substituted as described herein for aryl and alkyl, respectively.
  • arylalkoxy represents a substituent of formula -OR, where R is arylalkyl.
  • R is arylalkyl.
  • the arylalkyl is optionally substituted as described herein for aryl alkyl.
  • aryloxy represents a chemical substituent of formula -OR, where R is aryl.
  • R is aryl.
  • the aryl group is optionally substituted as described herein for aryl.
  • CBP represents a CREB-binding protein (e.g., a human CREB- binding protein) having a KIX domain.
  • Exemplary CBP protein sequences are given by NCBI Reference Sequences: NP_004371 .2 (isoform a) and NP 001073315.1 (isoform b).
  • Cx-y indicates that the group, the name of which immediately follows the expression, when unsubstituted, contains a total of from x to y carbon atoms. If the group is a composite group (e.g., aryl alkyl), Cx- y indicates that the portion, the name of which immediately follows the expression, when unsubstituted, contains a total of from x to y carbon atoms.
  • (Ce-io- aryl)-Ci-6-alkyl is a group, in which the aryl portion, when unsubstituted, contains a total of from 6 to 10 carbon atoms, and the alkyl portion, when unsubstituted, contains a total of from 1 to 6 carbon atoms.
  • cycloalkyl represents a monovalent, cyclic, non-aromatic, hydrocarbon group having from three to ten carbons, unless otherwise specified.
  • Cycloalkyl groups may be monocyclic, bicyclic, spirocyclic, or caged (e.g., adamantyl).
  • Fused bicyclic cycloalkyl groups may be of bicyclo[p.q.0]alkyl type, in which each of p and q is, independently, 1 , 2, 3, 4, 5, 6, or 7, provided that the sum of p and q is 2, 3, 4, 5, 6, 7, or 8.
  • fused bicyclic cycloalkyl groups may include bridged cycloalkyl structures, e.g., bicyclo[p.q.r]alkyl, in which r is 1 , 2, or 3, each of p and q is, independently, 1 , 2, 3, 4, 5, or 6, provided that the sum of p, q, and r is 3, 4, 5, 6, 7, or 8.
  • the spirocyclic cycloalkyl group may be spiro[p.q]alkyl, in which each of p and q is, independently, 2, 3, 4, 5, 6, or 7, provided that the sum of p and q is 4, 5, 6, 7, 8, or 9. Cycloalkyl may be saturated or unsaturated.
  • An unsaturated cycloalkyl contains one or two carbon-carbon double bonds.
  • Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohex-1 -enyl, cyclohex-2-enyl, cyclohex-3-enyl, cycloheptyl, 1 -bicyclo[2.2.1 ]heptyl, 2-bicyclo[2.2.1 ]heptyl, 5-bicyclo[2.2.1 ]heptyl, 7- bicyclo[2.2.1 ]heptyl, and decalinyl.
  • the cycloalkyl group may be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of: alkyl; alkoxy; acyloxy; aryloxy; arylalkoxy; cycloalkyl; cycloalkoxy; halogen; haloalkyl; haloalkoxy; heterocyclyl; heteroaryl;
  • cycloalkoxy represents a group -OR, where R is cycloalkyl.
  • haloalkyl represents an alkyl substituted with one or more halogens (e.g., fluorine) as described herein.
  • halogens e.g., fluorine
  • Non-limiting examples of haloalkyl include trifluoromethyl, 2,2,2- trifluoroethyl, and pentafluoroethyl.
  • haloalkoxy represents a substituent -OR, where R is haloalkyl.
  • haloaryl represents an aryl substituted with 1 , 2, or 3 groups independently selected from halogens.
  • halogen represents bromine, chlorine, iodine, or fluorine.
  • heteroaryl represents a monocyclic, bicyclic, tricyclic, or tetracyclic ring system having fused or bridging 5-, 6-, 7-, or 8-membered rings, the ring system containing one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; where at least one of the rings is an aromatic ring.
  • heteroaryl groups include benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, furyl, imidazolyl, indolyl, isoindazolyl, isoquinolinyl, isothiazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, purinyl, pyrrolyl, pyridinyl, pyrazinyl, pyrimidinyl, qunazolinyl, quinolinyl, thiadiazolyl (e.g., 1 ,3,4-thiadiazole), thiazolyl, thienyl, triazolyl, tetrazolyl, dihydroindolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, etc.
  • bicyclic, tricyclic, and tetracyclic heteroaryls include at least one ring having at least one heteroatom as described above and at least one aromatic ring; the at least one heteroatom may be present in the at least one aromatic ring.
  • a ring having at least one heteroatom may be fused to one, two, or three carbocyclic rings, e.g., an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring, or another monocyclic heterocyclic ring.
  • fused heteroaryls examples include 1 ,2,3,5,8,8a-hexahydroindolizine; 2,3-dihydrobenzofuran; 2,3-dihydroindole; and 2,3- dihydrobenzothiophene.
  • heteroaryloxy represents a group -OR, where R is heteroaryl.
  • heterocyclyl represents a monocyclic, bicyclic, tricyclic, or tetracyclic non-aromatic ring system having fused or bridging 4-, 5-, 6-, 7-, or 8-membered rings, unless otherwise specified, the ring system containing one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
  • Non-aromatic 5-membered heterocyclyl has zero or one double bonds
  • non-aromatic 6- and 7-membered heterocyclyl groups have zero to two double bonds
  • non-aromatic 8-membered heterocyclyl groups have zero to two double bonds and/or zero or one carbon- carbon triple bond.
  • Heterocyclyl groups have a carbon count of 1 to 16 carbon atoms unless otherwise specified. Certain heterocyclyl groups may have a carbon count up to 9 carbon atoms.
  • Non-aromatic heterocyclyl groups include pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, homopiperidinyl, piperazinyl, pyridazinyl, oxazolidinyl, isoxazolidiniyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, thiazolidinyl, tetrahydrofuranyl, dihydrofuranyl,
  • heterocyclyl also represents a heterocyclic compound having a bridged multicyclic structure in which one or more carbons and/or heteroatoms bridges two non-adjacent members of a monocyclic ring, e.g., quinuclidine, tropanes, or diaza-bicyclo[2.2.2]octane.
  • heterocyclyl includes bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings is fused to one, two, or three carbocyclic rings, e.g., a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring, or another heterocyclic ring.
  • fused heterocyclyls include 1 ,2,3,5,8,8a-hexahydroindolizine; 2,3-dihydrobenzofuran; 2,3-dihydroindole; and 2,3-dihydrobenzothiophene.
  • the heterocyclyl group may be unsubstituted or substituted with one, two, three, four or five substituents independently selected from the group consisting of: alkyl; alkoxy; acyloxy; aryl; aryl alkyl; aryloxy; aryloyl; arylalkyl; arylalkoxy;
  • cycloalkyl cycloalkoxy; halogen; haloalkyl; haloalkoxy; heterocyclyl; heteroaryl; heterocyclyloxy;
  • any of the optional substituents described for heterocyclyl may be further optionally substituted with unsubstituted substituent(s) as described herein for each respective substituent.
  • a C1-9 heterocyclyl may be optionally substituted with alkoxyaryl or haloaryl.
  • heterocyclyl alkyl represents an alkyl group substituted with one or two heterocyclyl group(s).
  • each of the heterocyclyl and alkyl portions may be independently, optionally substituted as described herein for heterocyclyl and alkyl, respectively.
  • heterocyclyloxy represents a group -OR, where R is heterocyclyl.
  • inhibitor refers to a reduction in the binding between a target protein and another protein by a compound at an IC50 sufficient to elicit a desired phenotypic response (e.g., cell death) in a cell (e.g., at an IC50 of 1 mM or less (e.g., 500 mM or less, 300 mM or less, 200 mM or less,
  • MED15 represents a mediator of RNA polymerase II transcription subunit 15 protein (e.g., a human mediator of RNA polymerase II transcription subunit 15 protein) having a KIX domain.
  • exemplary MED15 protein sequences are given by NCBI Reference Sequences:
  • NP_001 003891 .1 (isoform a), NP_056973.2 (isoform b), NP_001280163.1 (isoform c), NP_001280164.1 (isoform d), and NP 001280165.1 (isoform e).
  • pharmaceutically acceptable refers to those compounds, materials, compositions, and/or dosage forms, which are suitable for contact with the tissues of an individual (e.g., a human), without excessive toxicity, irritation, allergic response and other problem complications commensurate with a reasonable benefit/risk ratio.
  • salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al. , J. Pharmaceutical Sciences 66:1 -19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008.
  • the salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting the free base group with a suitable organic acid.
  • Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate,
  • benzenesulfonate benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
  • protecting group represents a group intended to protect a hydroxy, an amino, or a carbonyl from participating in one or more undesirable reactions during chemical synthesis.
  • O-protecting group represents a group intended to protect a hydroxy or carbonyl group from participating in one or more undesirable reactions during chemical synthesis.
  • /V-protecting group represents a group intended to protect a nitrogen containing (e.g., an amino or hydrazine) group from participating in one or more undesirable reactions during chemical synthesis.
  • O- and /V-protecting groups are disclosed in Greene,“Protective Groups in Organic Synthesis,” 3 rd Edition (John Wiley & Sons, New York, 1999), which is incorporated herein by reference.
  • Exemplary O- and /V-protecting groups include alkanoyl, aryloyl, or carbamyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, f-butyldimethylsilyl, tri-/ ' so-propylsilyloxymethyl, 4,4'-dimethoxytrityl, isobuty
  • O-protecting groups for protecting carbonyl containing groups include, but are not limited to: acetals, acylals, 1 ,3-dithianes, 1 ,3-dioxanes, 1 ,3-dioxolanes, and 1 ,3-dithiolanes.
  • O-protecting groups include, but are not limited to: substituted alkyl, aryl, and aryl-alkyl ethers (e.g., trityl; methylthiomethyl; methoxymethyl; benzyloxymethyl; siloxymethyl; 2,2,2,- trichloroethoxymethyl; tetrahydropyranyl; tetrahydrofuranyl; ethoxyethyl; 1 -[2-(trimethylsilyl)ethoxy]ethyl; 2-trimethylsilylethyl; t-butyl ether; p-chlorophenyl, p-methoxyphenyl, p-nitrophenyl, benzyl, p- methoxybenzyl, and nitrobenzyl); silyl ethers (e.g., trimethylsilyl; triethylsilyl; triisopropylsilyl;
  • silyl ethers e.g., tri
  • diphenymethylsilyl diphenymethylsilyl
  • carbonates e.g., methyl, methoxymethyl, 9-fluorenylmethyl; ethyl; 2,2,2- trichloroethyl; 2-(trimethylsilyl)ethyl; vinyl, allyl, nitrophenyl; benzyl; methoxybenzyl; 3,4-dimethoxybenzyl; and nitrobenzyl).
  • /V-protecting groups include, but are not limited to, chiral auxiliaries such as protected or unprotected D, L or D, L-amino acids such as alanine, leucine, phenylalanine, and the like; sulfonyl- containing groups such as benzenesulfonyl, p-toluenesulfonyl, and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p- nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4- dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyl oxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxy
  • diisopropylmethoxycarbonyl isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxy carbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl, and the like, aryl-alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl, and the like and silyl groups such as trimethylsilyl, and the like.
  • SREBP Sterol Regulatory Element-binding Protein 1
  • NP 001005291 .1 isoform a
  • NP_004167.3 isoform b
  • SREBP is SREBP isoform a.
  • subject represents a human or non-human animal (e.g., a mammal) that is suffering from, or is at risk of, a disease or condition, as determined by a qualified professional (e.g., a doctor or a nurse practitioner) with or without known in the art laboratory test(s) of sample(s) from the patient.
  • a qualified professional e.g., a doctor or a nurse practitioner
  • Treatment and “treating,” as used herein, refer to the medical management of a subject with the intent to improve, ameliorate, stabilize, prevent or cure a disease or condition. This term includes active treatment (treatment directed to improve the disease or condition); causal treatment (treatment directed to the cause of the associated disease or condition); palliative treatment (treatment designed for the relief of symptoms of the disease or condition); preventative treatment (treatment directed to minimizing or partially or completely inhibiting the development of the associated disease or condition); and supportive treatment (treatment employed to supplement another therapy).
  • the compounds described herein encompass isotopically enriched compounds (e.g., deuterated compounds), tautomers, and all stereoisomers and conformers (e.g.
  • FIG. 1 A is a chart showing the ATP production normalized to the DMSO control being a proxy for the cell viability as a function of the compound concentration.
  • FIG. 1 B is a chart showing the ATP production normalized to the DMSO control being a proxy for the cell viability as a function of the compound concentration.
  • FIG. 2A is a chart showing the approximate concentrations of SCD1 , HMGCR, and FASN transcripts normalized to the DMSO control as a function of the compound concentration.
  • FIG. 2B is a chart showing the approximate concentrations of SCD1 , HMGCR, and FASN transcripts normalized to the DMSO control as a function of the compound concentration.
  • FIG. 3A is a graph showing normalized luciferase reading observed for X1 in a FASN-luciferase assay.
  • FIG. 3B is a graph showing P32 dose-dependent reduction in the normalized luciferase readings.
  • FIG. 4A is a graph showing Cell Titer-Glo (CTG) signal level normalized to a vehicle control in response to P32, P28, or P22.
  • CCG Cell Titer-Glo
  • FIG. 4B is a graph showing the fold-change in the transcript abundance in cells incubated with a vehicle, P32, P28, or P22. The data are normalized to the transcript abundance in cells incubated with a vehicle.
  • FIG. 5A is a graph showing Cell Titer-Glo signal level normalized to a vehicle control in response to X1 , A30, and A7.
  • FIG. 5B is a graph showing the fold-change in the transcript abundance in cells incubated with a vehicle, X1 , A30, and A7. The data are normalized to the transcript abundance in cells incubated with a vehicle.
  • FIG. 6A is a Kaplan-Meier survival plot for mice implanted with MGG8 cells and treated with DMSO (control), P32, or X1 .
  • FIG. 6B is a Kaplan-Meier survival plot for mice implanted with U251 -MG cells and treated with DMSO (control) or A1 .
  • FIG. 7 is a chart showing cell viability assay results for P32 and X1 .
  • Glioblastomas (GBMs) carrying EGFR activating mutations have increased SREBP activity and activation of lipogenic gene expression. Inhibition of SREBP is shown to induce GBM cell death.
  • FIG. 8A is a chart assessing ATP product and caspase 3/7 levels in cells transfected with siRNA targeting SREBF1 , SREBF2, or both SREBF1 and SREBF2 relative to non-transfected cells (NT).
  • FIG. 8B is a chart showing SREBF1 and SREBF2 transcript abundance in cells transfected with siRNA targeting SREBF1 , SREBF2, or both SREBF1 and SREBF2. The data are normalized to the RPLP0 transcript levels.
  • FIG. 8C is a chart showing SCD1 , FASN, and HMGCR transcript abundance in cells transfected with siRNA targeting SREBF1 , SREBF2, or both SREBF1 and SREBF2. The data are normalized to the RPLP0 transcript levels.
  • FIG. 9A is a chart showing the SCD1 , HMGCR, FASN, ACC, and SREBF1 transcript abundance in cells treated with DMSO or P32. The data are normalized to the b-actin levels and the DMSO control.
  • FIG. 9B is a chart showing the SCD1 , HMGCR, FASN, ACC, and SREBF1 transcript abundance in cells treated with DMSO or P1 .
  • the data are normalized to the b-actin levels and the DMSO control.
  • FIG. 10A is a chart showing the SCD1 , HMGCR, FASN, ACC, and SREBF1 transcript abundance in cells treated with DMSO or X1 .
  • the data are normalized to the b-actin levels and the DMSO control.
  • FIG. 10B is a chart showing the SCD1 , HMGCR, FASN, ACC, and SREBF1 transcript abundance in cells treated with DMSO or A1 .
  • the data are normalized to the b-actin levels and the DMSO control.
  • FIG. 1 1 A is a chart showing CTG signal curves for A1 , X1 , and P32 in 10% FBS. The signal is normalized to DMSO.
  • FIG. 1 1 B is a chart showing CTG signal curves for A1 , X1 , and P32 in 1 % LDPS. The signal is normalized to DMSO.
  • FIG. 12 is a chart showing CTG signal levels observed in cancer cells treated with X1 .
  • FIG. 13 is a chart showing changes in the SCD1 , FASN, and HMGCR transcript abundance in cells treated with P32. The data are normalized to the b-actin levels and the vehicle control.
  • FIG. 14 is a chart showing changes in the SCD1 , FASN, and HMGCR transcript abundance in cells treated with X1 . The data are normalized to the b-actin levels and the vehicle control.
  • FIG. 15A is a chart showing dose dependent CTG and caspase glo responses to P32.
  • the Y- axis on the right corresponds to the CTG response normalized to the DMSO control, and the Y-axis on the left corresponds to the caspase glo response normalized to the DMSO control.
  • FIG. 15B is a chart showing dose dependent CTG and caspase glo signals to X1 .
  • the Y-axis on the right corresponds to the CTG signal normalized to the DMSO control, and the Y-axis on the left corresponds to the caspase glo signal normalized to the DMSO control.
  • FIG. 16A is a chart showing dose dependent, normalized CTG signal levels in RCC-AB cells treated with varying concentrations of erastin and P32. The data are normalized to DMSO.
  • the X-axis shows P32 concentrations (mM).
  • FIG. 16B is a chart showing Bliss synergy scores for P32/erastin combination therapy in RCC-AB cells. The max score was 15.53.
  • FIG. 17A is a chart showing dose dependent, normalized CTG signal levels in RCC-FG2 cells treated with varying concentrations of erastin and P32. The data are normalized to DMSO. The X-axis shows P32 concentrations (pM).
  • FIG. 17B is a chart showing Bliss synergy scores for P32/erastin combination therapy in RCC- FG2 cells.
  • the max score was 22.09.
  • FIG. 18A is a chart showing dose dependent, normalized CTG signal levels in RCC-JF cells treated with varying concentrations of erastin and P32. The data are normalized to DMSO. The X-axis shows P32 concentrations (pM).
  • FIG. 18B is a chart showing Bliss synergy scores for P32/erastin combination therapy in RCC-JF cells. The max score was 37.2.
  • FIG. 19A is a chart showing dose dependent, normalized CTG signal levels in RCC-AB cells treated with varying concentrations of erastin and X1 .
  • the data are normalized to DMSO.
  • the X-axis shows X1 concentrations (pM).
  • FIG. 19B is a chart showing Bliss synergy scores for X1 /erastin combination therapy in RCC-AB cells. The max score was -2.24.
  • FIG. 20A is a chart showing dose dependent, normalized CTG signal levels in RCC-FG2 cells treated with varying concentrations of erastin and X1 .
  • the data are normalized to DMSO.
  • the X-axis shows X1 concentrations (pM).
  • FIG. 20B is a chart showing Bliss synergy scores for X1 /erastin combination therapy in RCC-FG2 cells.
  • the max score was 16.41 .
  • FIG. 21 A is a chart showing dose dependent, normalized CTG signal levels in RCC-JF cells treated with varying concentrations of erastin and X1 .
  • the data are normalized to DMSO.
  • the X-axis shows X1 concentrations (pM).
  • FIG. 21 B is a chart showing Bliss synergy scores for X1 /erastin combination therapy in RCC-JF cells. The max score was 24.2.
  • FIG. 22A is a chart showing dose dependent, normalized CTG signal levels in U251 -MG cells treated with varying concentrations of erastin and P32. The data are normalized to DMSO.
  • FIG. 22B is a projection plot showing Bliss synergy scores for P32/erastin combination therapy in U251 -MG cells.
  • FIG. 22C is a chart showing Bliss synergy scores for X1 /erastin combination therapy in U251 -MG cells.
  • FIG. 23A is a chart showing dose dependent, normalized CTG signal levels in U251 -MG cells treated with varying concentrations of erastin and X1 . The data are normalized to DMSO.
  • FIG. 23B is a projection plot showing Bliss synergy scores for X1 /erastin combination therapy in U251 -MG cells.
  • FIG. 23C is a chart showing Bliss synergy scores for X1 /erastin combination therapy in U251 -MG cells.
  • FIG. 24A is a chart showing Bliss synergy scores for P32/666-15 combination therapy in RCC-JF cells in FBS. The max score was 18.8.
  • FIG. 24B is a chart showing Bliss synergy scores for P32/666-15 combination therapy in RCC-JF cells in LDPS.
  • the max score was 6.2.
  • FIG. 25A is a chart showing Bliss synergy scores for P32/fatostatin combination therapy in RCC- JF cells in FBS.
  • the max score was 12.34.
  • FIG. 25B is a chart showing Bliss synergy scores for P32/fatostatin combination therapy in RCC- JF cells in LDPS.
  • the max score was 5.88.
  • FIG. 26A is a chart showing Bliss synergy scores for P32/A-485 combination therapy in RCC-JF cells in FBS.
  • the max score was 10.4.
  • FIG. 26B is a chart showing Bliss synergy scores for P32/ A-485 combination therapy in RCC-JF cells in LDPS.
  • the max score was 8.52.
  • FIG. 27A is a chart showing Bliss synergy scores for P32/PF429242 combination therapy in RCC-JF cells in FBS.
  • the max score was 2.66.
  • FIG. 27B is a chart showing Bliss synergy scores for P32/ PF429242 combination therapy in RCC-JF cells in LDPS.
  • the max score was 3.04.
  • FIG. 28A is a chart showing Bliss synergy scores for X1/666-15 combination therapy in RCC-JF cells in FBS. The max score was 13.2.
  • FIG. 28B is a chart showing Bliss synergy scores for X1/666-15 combination therapy in RCC-JF cells in LDPS.
  • the max score was 4.05.
  • FIG. 29A is a chart showing Bliss synergy scores for X1/fatostatin combination therapy in RCC- JF cells in FBS.
  • the max score was 1 1 .83.
  • FIG. 29B is a chart showing Bliss synergy scores for X1/fatostatin combination therapy in RCC- JF cells in LDPS.
  • the max score was 13.37.
  • FIG. 30A is a chart showing Bliss synergy scores for X1 /A-485 combination therapy in RCC-JF cells in FBS.
  • the max score was 2.56.
  • FIG. 30B is a chart showing Bliss synergy scores for X1 / A-485 combination therapy in RCC-JF cells in LDPS. The max score was 0.98.
  • FIG. 31 A is a chart showing Bliss synergy scores for X1/PF429242 combination therapy in RCC- JF cells in FBS.
  • the max score was 1 .067.
  • FIG. 31 B is a chart showing Bliss synergy scores for X1 / PF429242 combination therapy in RCC- JF cells in LDPS.
  • the max score was 4.64.
  • FIG. 32A is a chart showing CTG signal levels for U251 -MG cells treated with P32 with or without a fatty acid (FA), SyntheChol (SC), or FA and SC supplement. The data are normalized to DMSO control.
  • FIG. 32B is a chart showing CTG signal levels for U251 -MG cells treated with X1 with or without a fatty acid (FA), SyntheChol (SC), or FA and SC supplement. The data are normalized to DMSO control.
  • FA fatty acid
  • SC SyntheChol
  • FIG. 33 is a chart showing the results for the Chlp-qPCR assay examining the enrichment of MED1 on indicated gene loci.
  • the enrichment of MED1 at promoter of typical SREBP-target genes ( FASN , SCD and HMGCR) induced by switching to 1 %LPDS medium was abolished after the treatment of P32 or X1 .
  • the p-value was calculated by ANOVA followed by Dunnett's multiple comparisons test (1 %LPDS condition as the control) p ⁇ 0.0001 **** , p ⁇ 0.001 *** , p ⁇ 0.01 ** , p ⁇ 0.05 * , p>0.05 n.s.
  • FIG. 34 is a chart showing the results for the Chlp-qPCR assay examining the enrichment of Pol II on indicated gene loci.
  • the enrichment of Pol II at promoter of typical SREBP-target genes ( FASN , SCD and HMGCR) induced by switching to 1 %LPDS medium was abolished after the treatment of C2 or C34.
  • the p-value was calculated by ANOVA followed by Dunnett's multiple comparisons test (1 %LPDS condition as the control) p ⁇ 0.0001 **** , p ⁇ 0.001 *** , p ⁇ 0.01 ** , p ⁇ 0.05 * , p>0.05 n.s.
  • the invention provides compounds, pharmaceutical compositions containing them, and methods of their use in the treatment of diseases treatable through inhibition of an interaction between sterol regulatory element-binding protein 1 (SREBP1 ) and the KIX domain of mediator of RNA polymerase II transcription subunit 15 (MED15) or CREB-binding protein (CBP) (e.g., cancer or metabolic disorder).
  • SREBP1 sterol regulatory element-binding protein 1
  • MED15 mediator of RNA polymerase II transcription subunit 15
  • CBP CREB-binding protein
  • compounds of the invention are believed to inhibit the interaction between SREBP1 and the KIX domain of CBP or MED15.
  • the invention provides compounds that may be useful in the treatment of cancers or metabolic disorders.
  • the compound may be an agent capable of inhibiting the binding of SREBP1 and the KIX domain of CBP or MED15 to inhibit the binding between SREBP1 and the KIX domain of MED15 or CBP.
  • the agent may be a small molecule or an antibody capable of binding the KIX domain of CBP or MED15 to inhibit the binding between SREBP1 and the KIX domain of MED15 or CBP.
  • a small molecule of the invention may be a compound of formula (I):
  • n 1 , 2, 3, 4, or 5;
  • each R 1 is independently optionally substituted C3-10 cycloalkyl, optionally substituted C1-6 alkyl, optionally substituted C1 -9 heterocyclyl, halogen, optionally substituted C1 -6 alkoxy, optionally substituted C2-6 alkenyloxy, optionally substituted C2-6 alkynyloxy, or optionally substituted Ce-io aryloxy; and
  • R 2 is hydroxyl, optionally substituted C1 -6 alkoxy, or -N(R 3 )2, wherein each R 3 is independently H, optionally substituted C1 -6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-10 cycloalkyl, optionally substituted Ce-io aryl C1-6 alkyl, or optionally substituted C1-9 heterocyclyl C1-6 alkyl, or both R 3 , together with the atom to which they are attached, combine to form an optionally substituted C1 -9 heterocyclyl.
  • the compound of formula (I) is not a compound of any one of the following compounds:
  • the compound of formula (I) is a compound of formula (IA):
  • the compound of formula (I) is a compound of formula (IB):
  • a small molecule compound of the invention may be a compound of formula (II):
  • n 0, 1 , or 2;
  • Z is -SO2- or -S-;
  • R 1 is -COOR A or -CONR B R c ;
  • each R 2 when present, is independently halogen
  • R 3 is optionally substituted Ce-io aryl C1 -6 alkyl or optionally substituted C1 -6 alkyl;
  • R A is H or optionally substituted C1 -6 alkyl
  • R B is optionally substituted Ce-io aryl, optionally substituted Ce-io aryl C1-6 alkyl, optionally substituted 5-membered heteroaryl, optionally substituted bicyclic heteroaryl, optionally substituted C1-9 heterocyclyl, or optionally substituted C1 -9 heterocyclyl C1-6 alkyl; and R c is H or optionally substituted C1-6 alkyl; or R B and R c combine to form an optionally substituted C1 -9 heterocyclyl.
  • the compound of formula (II) is not a compound of any one of the following compounds:
  • the compound of formula (II) is a compound of formula (II A) :
  • a small molecule may be a compound selected from the group consisting of:
  • An agent of the invention may be an antibody or an antigen-binding fragment thereof.
  • a target antigen e.g., KIX domain of CBP or MED15
  • Zhiqiang An Editor
  • Therapeutic Monoclonal Antibodies From Bench to Clinic. 1 st Edition. Wiley 2009, and also Greenfield (Ed.), Antibodies: A Laboratory Manual.
  • compositions including antibody engineering, use of degenerate oligonucleotides, 5'-RACE, phage display, and mutagenesis; antibody testing and characterization; antibody pharmacokinetics and pharmacodynamics; antibody purification and storage; and screening and labeling techniques.
  • compositions typically include a compound as described herein and a pharmaceutically acceptable excipient.
  • the compound is a compound of formula (I) (e.g., a compound selected from the group consisting of compounds A1-A40, or a compound selected from the group consisting of compounds X1-X5).
  • the compound is a compound of formula (II) (e.g., a compound selected from the group consisting of compounds P1-P57).
  • the compounds described herein can also be used in the form of the free base, in the form of salts, zwitterions, solvates, or as prodrugs, or pharmaceutical compositions thereof. All forms are within the scope of the invention.
  • the compounds, salts, zwitterions, solvates, prodrugs, or pharmaceutical compositions thereof may be administered to a patient in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art.
  • the compounds used in the methods described herein may be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump, or transdermal administration, and the pharmaceutical compositions formulated accordingly.
  • Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration may be by continuous infusion over a selected period of time.
  • compositions for use in accordance with the present invention thus can be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries that facilitate processing of a compound of the invention into preparations which can be used pharmaceutically.
  • compositions which can contain one or more pharmaceutically acceptable carriers.
  • the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container.
  • the excipient serves as a diluent, it can be a solid, semisolid, or liquid material (e.g., normal saline), which acts as a vehicle, carrier or medium for the active ingredient.
  • the compositions can be in the form of tablets, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, and soft and hard gelatin capsules.
  • the type of diluent can vary depending upon the intended route of administration.
  • the resulting compositions can include additional agents, e.g., preservatives.
  • the excipient or carrier is selected on the basis of the mode and route of administration. Suitable pharmaceutical carriers, as well as pharmaceutical necessities for use in pharmaceutical formulations, are described in Remington: The Science and Practice of Pharmacy, 21 st Ed., Gennaro, Ed., Lippincott Williams & Wilkins (2005), a well-known reference text in this field, and in the USP/NF (United States Pharmacopeia and the National Formulary).
  • excipients examples include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose.
  • the formulations can additionally include: lubricating agents, e.g., talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents, e.g., methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
  • lubricating agents e.g., talc, magnesium stearate, and mineral oil
  • wetting agents emulsifying and suspending agents
  • preserving agents e.g., methyl- and propylhydroxy-benzoates
  • sweetening agents and flavoring agents.
  • compositions can be manufactured in a conventional manner, e.g., by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes.
  • Methods well known in the art for making formulations are found, for example, in Remington: The Science and Practice of Pharmacy, 21 st Ed., Gennaro, Ed., Lippincott Williams & Wilkins (2005), and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1 988-1999, Marcel Dekker, New York. Proper formulation is dependent upon the route of administration chosen.
  • the formulation and preparation of such compositions is well-known to those skilled in the art of pharmaceutical formulation.
  • the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g., about 40 mesh.
  • the dosage of the compound used in the methods described herein, or pharmaceutically acceptable salts or prodrugs thereof, or pharmaceutical compositions thereof can vary depending on many factors, e.g., the pharmacodynamic properties of the compound; the mode of administration; the age, health, and weight of the recipient; the nature and extent of the symptoms; the frequency of the treatment, and the type of concurrent treatment, if any; and the clearance rate of the compound in the animal to be treated.
  • One of skill in the art can determine the appropriate dosage based on the above factors.
  • the compounds used in the methods described herein may be administered initially in a suitable dosage that may be adjusted as required, depending on the clinical response.
  • a suitable daily dose of a compound of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
  • a compound of the invention may be administered to the patient in a single dose or in multiple doses. When multiple doses are administered, the doses may be separated from one another by, for example, 1 -24 hours, 1 -7 days, 1 -4 weeks, or 1 -12 months.
  • the compound may be administered according to a schedule or the compound may be administered without a predetermined schedule.
  • An active compound may be administered, for example, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , or 12 times per day, every 2 nd , 3 rd , 4 th , 5 th , or 6 th day, 1 , 2, 3, 4, 5, 6, or 7 times per week, 1 , 2, 3, 4, 5, or 6 times per month, or 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , or 12 times per year. It is to be understood that, for any particular subject, specific dosage regimes should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.
  • an effective amount of a compound of the invention may be, for example, a total daily dosage of, e.g., between 0.05 mg and 3000 mg of any of the compounds described herein.
  • the dosage amount can be calculated using the body weight of the patient.
  • Such dose ranges may include, for example, between 10-1000 mg (e.g., 50-800 mg).
  • 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg of the compound is administered.
  • the time period during which multiple doses of a compound of the invention are administered to a patient can vary.
  • doses of the compounds of the invention are administered to a patient over a time period that is 1 -7 days; 1 -12 weeks; or 1 -3 months.
  • the compounds are administered to the patient over a time period that is, for example, 4-1 1 months or 1 -30 years.
  • the compounds are administered to a patient at the onset of symptoms.
  • the amount of compound that is administered may vary during the time period of administration. When a compound is administered daily, administration may occur, for example, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , or 12 times per day.
  • a compound identified as capable of treating any of the conditions described herein, using any of the methods described herein, may be administered to patients or animals with a pharmaceutically- acceptable diluent, carrier, or excipient, in unit dosage form.
  • the chemical compounds for use in such therapies may be produced and isolated by any standard technique known to those in the field of medicinal chemistry.
  • Conventional pharmaceutical practice may be employed to provide suitable formulations or compositions to administer the identified compound to patients suffering from a bacterial infection. Administration may begin before the patient is symptomatic.
  • Exemplary routes of administration of the compounds include oral, sublingual, buccal, transdermal, intradermal, intramuscular, parenteral, intravenous, intra-arterial, intracranial, subcutaneous, intraorbital, intraventricular, intraspinal, intraperitoneal, intranasal, inhalation, and topical administration.
  • the compounds desirably are administered with a pharmaceutically acceptable carrier.
  • Pharmaceutical formulations of the compounds described herein formulated for treatment of the disorders described herein are also part of the present invention.
  • oral dosage forms can be, for example, in the form of tablets, capsules, a liquid solution or suspension, a powder, or liquid or solid crystals, which contain the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients.
  • excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates, or alginic acid); binding agents (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate,
  • inert diluents or fillers e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lac
  • lubricating agents e.g., magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenated vegetable oils, or talc.
  • Other pharmaceutically acceptable excipients can be colorants, flavoring agents, plasticizers, humectants, buffering agents, and the like.
  • Formulations for oral administration may also be presented as chewable tablets, as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example, peanut oil, liquid paraffin, or olive oil.
  • Powders, granulates, and pellets may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using, e.g., a mixer, a fluid bed apparatus or a spray drying equipment.
  • Controlled release compositions for oral use may be constructed to release the active drug by controlling the dissolution and/or the diffusion of the active drug substance. Any of a number of strategies can be pursued in order to obtain controlled release and the targeted plasma concentration versus time profile.
  • controlled release is obtained by appropriate selection of various formulation parameters and ingredients, including, e.g., various types of controlled release compositions and coatings. Examples include single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, nanoparticles, patches, and liposomes.
  • compositions include biodegradable, pH, and/or temperature-sensitive polymer coatings.
  • Dissolution or diffusion controlled release can be achieved by appropriate coating of a tablet, capsule, pellet, or granulate formulation of compounds, or by incorporating the compound into an appropriate matrix.
  • a controlled release coating may include one or more of the coating substances mentioned above and/or, e.g., shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glycerol palmitostearate, ethylcellulose, acrylic resins, dl- polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone, polyethylene, polymethacrylate, methylmethacrylate, 2-hydroxymethacrylate, methacrylate hydrogels, 1 ,3 butylene glycol, ethylene glycol methacrylate, and/or polyethylene glycols.
  • the matrix material may also include, e.g., hydrated methylcellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, and/or halogenated fluorocarbon.
  • liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils, e.g., cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • aqueous solutions suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils, e.g., cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • Dosages for buccal or sublingual administration typically are 0.1 to 500 mg per single dose as required.
  • the physician determines the actual dosing regimen which is most suitable for an individual patient, and the dosage varies with the age, weight, and response of the particular patient.
  • the above dosages are exemplary of the average case, but individual instances exist wherein higher or lower dosages are merited, and such are within the scope of this invention.
  • compositions may take the form of tablets, lozenges, etc.
  • Liquid drug formulations suitable for use with nebulizers and liquid spray devices and electrohydrodynamic (EHD) aerosol devices will typically include a compound of the invention with a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier is a liquid, e.g., alcohol, water, polyethylene glycol, or a perfluorocarbon.
  • another material may be added to alter the aerosol properties of the solution or suspension of compounds of the invention. Desirably, this material is liquid, e.g., an alcohol, glycol, polyglycol, or a fatty acid.
  • compositions for nasal administration also may conveniently be formulated as aerosols, drops, gels, and powders.
  • the formulations may be provided in a single or multidose form.
  • dosing may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension.
  • this may be achieved, for example, by means of a metering atomizing spray pump.
  • the compounds may further be formulated for aerosol administration, particularly to the respiratory tract by inhalation and including intranasal administration.
  • the compound will generally have a small particle size for example on the order of five (5) microns or less. Such a particle size may be obtained by means known in the art, for example by micronization.
  • the active ingredient is provided in a pressurized pack with a suitable propellant, e.g., a chlorofluorocarbon (CFC), for example,
  • the aerosol may conveniently also contain a surfactant, e.g., lecithin.
  • the dose of drug may be controlled by a metered valve.
  • the active ingredients may be provided in a form of a dry powder, e.g., a powder mix of the compound in a suitable powder base, e.g., lactose, starch, and starch derivatives, e.g., hydroxypropylmethyl cellulose, and polyvinylpyrrolidine (PVP).
  • the powder carrier will form a gel in the nasal cavity.
  • the powder composition may be presented in unit dose form for example in capsules or cartridges of e.g., gelatin or blister packs from which the powder may be administered by means of an inhaler.
  • Aerosol formulations typically include a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomizing device.
  • the sealed container may be a unitary dispensing device, e.g., a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal after use.
  • the dosage form comprises an aerosol dispenser, it will contain a propellant, which can be a compressed gas, e.g., compressed air or an organic propellant, e.g.,
  • the aerosol dosage forms can also take the form of a pump-atomizer.
  • compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the compounds of the invention may be dissolved or suspended in a parenterally acceptable liquid vehicle.
  • acceptable vehicles and solvents water, water adjusted to a suitable pH by addition of an appropriate amount of hydrochloric acid, sodium hydroxide or a suitable buffer, 1 ,3-butanediol, Ringer’s solution and isotonic sodium chloride solution.
  • the aqueous formulation may also contain one or more preservatives, for example, methyl, ethyl, or n-propyl p-hydroxybenzoate. Additional information regarding parenteral formulations can be found, for example, in the United States Pharmacopeia-National Formulary (USP-NF), herein incorporated by reference.
  • USP-NF United States Pharmacopeia-National Formulary
  • the parenteral formulation can be any of the five general types of preparations identified by the USP-NF as suitable for parenteral administration:
  • drug for Injection the drug substance (e.g., a compound of the invention) as a dry solid that will be combined with the appropriate sterile vehicle for parenteral administration as a drug injection;
  • “Drug Injectable Emulsion” a liquid preparation of the drug substance (e.g., a compound of the invention) that is dissolved or dispersed in a suitable emulsion medium;
  • “Drug Injectable Suspension” a liquid preparation of the drug substance (e.g., a compound of the invention) suspended in a suitable liquid medium;
  • Exemplary formulations for parenteral administration include solutions of the compound prepared in water suitably mixed with a surfactant, e.g., hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.
  • Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington: The Science and Practice of Pharmacy, 21 st Ed., Gennaro, Ed., Lippincott Williams & Wilkins (2005) and in The United States Pharmacopeia: The National Formulary (USP 36 NF31 ), published in 2013.
  • Formulations for parenteral administration may, for example, contain excipients, sterile water, or saline, polyalkylene glycols, e.g., polyethylene glycol, oils of vegetable origin, or hydrogenated napthalenes.
  • polyalkylene glycols e.g., polyethylene glycol, oils of vegetable origin, or hydrogenated napthalenes.
  • polyoxyethylene-polyoxypropylene copolymers may be used to control the release of the compounds.
  • Other potentially useful parenteral delivery systems for compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes.
  • Formulations for inhalation may contain excipients, for example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or may be oily solutions for administration in the form of nasal drops, or as a gel.
  • the parenteral formulation can be formulated for prompt release or for sustained/extended release of the compound.
  • exemplary formulations for parenteral release of the compound include: aqueous solutions, powders for reconstitution, cosolvent solutions, oil/water emulsions, suspensions, oil- based solutions, liposomes, microspheres, and polymeric gels.
  • the invention also provides methods of use of the agents of the invention and their
  • a method of the invention is a method of treating cancer or a metabolic disorder in a subject in need thereof.
  • the method includes the step of administering a therapeutically effective amount of an agent of the invention or a pharmaceutical composition of the invention.
  • the cancer may be, e.g., melanoma, glioblastoma, glioma, prostate cancer, breast cancer, non-small cell lung cancer, or kidney cancer.
  • the metabolic disorder may be, e.g., nonalcoholic steatohepatitis or a cardiovascular disease (e.g., hypercholesterolemia).
  • a method of the invention is a method of inhibiting binding between SREBP1 and the KIX domain of MED15 or CBP in a subject in need thereof.
  • the method includes the step of administering a therapeutically effective amount of an agent of the invention or a pharmaceutical composition of the invention.
  • the compound or the pharmaceutical composition may be administered to the subject enterally (e.g., orally).
  • the compound or the pharmaceutical composition may be administered to the subject parenterally (e.g., intramuscularly, intratumorally, intravenously, subcutaneously, buccally, sublingually, sublabially, by inhalation, intra-arterially, intraventricularly, intraspinally, intrathecally, intraorbitally, intracranially, or topically).
  • a method of the invention is a method of killing a cancer cell.
  • this method includes a step of contacting a cancer cell with the compound of the invention.
  • the cancer cell may be in a subject (e.g., a human).
  • the compound is a compound of formula (I) (e.g., a compound selected from the group consisting of compounds A1-A40, or a compound selected from the group consisting of compounds X1-X5).
  • the compound is a compound of formula (II) (e.g., a compound selected from the group consisting of compounds P1-P57).
  • compounds disclosed herein may act synergistically with fatty acid/cholesterol homeostasis modulators or inducers of ferroprototic cell death in treating diseases, disorders, and conditions described herein or in killing cancer cells.
  • fatty acid/cholesterol homeostasis modulators include CREB/CBP-KIX inhibitors (e.g., 666-15), CBP/p300 HAT inhibitors (e.g., A-485), and SREBP1 site 1 protease inhibitors (e.g., PF429242).
  • Methods disclosed herein may further include the use of CREB/CBP-KIX inhibitors (e.g., 666-15), CBP/p300 HAT inhibitors (e.g., A-485), fatostatin, and SREBP1 site 1 protease inhibitors (e.g., PF429242), and pharmaceutically acceptable salts thereof.
  • CREB/CBP-KIX inhibitors e.g., 666-15
  • CBP/p300 HAT inhibitors e.g., A-485
  • fatostatin e.g., A-485
  • SREBP1 site 1 protease inhibitors e.g., PF429242
  • the compounds have the following structures:
  • Small molecules of the invention may be prepared using reactions and techniques known in the
  • R 1 and R 2 may be as described herein.
  • Friedel-Crafts reaction conditions e.g., in the presence of a Lewis acid (e.g., an oxophilic Lewis acid, such as AICI3)) to produce compound C.
  • a Lewis acid e.g., an oxophilic Lewis acid, such as AICI3
  • esterification if R 2 in D is optionally substituted alkoxy
  • amidation if R 2 in D is -N(R 3 )2
  • typical amidation conditions include the use of reagents, such as EDC/DMAP, EDC/HOBt, HATU/HOAt, or HBTU/HOAt.
  • the esterification reaction conditions are known in the art.
  • esterification conditions may include Steglich esterification (e.g., EDC/DMAP) or treatment with / ' so-butyl chloroformate and /V-methylmorpholine to prepare an intermediate mixed anhydride, which is then reacted with a nucleophile.
  • EDC may be provided, for example, as EDC- HCI or as EDCI.
  • Small molecules of the invention may be prepared using reactions and techniques known in the art. Non-limiting examples of the preparation of the small molecules are provided below. Compounds X1-X5 and P1 -P57 are commercially available.
  • a peptide corresponding to amino acids 17-42 of the SREBP-1 a activation domain was FITC- or TAMRA-labeled at the N-terminus with an AHA linker (sequences with FITC- and TAMRA-AHA- GPCDLDAALLTDIEDMLNLINNQDSD were generated by Tufts University Core Facility).
  • the peptide was solubilized in phosphate buffer (10.6 mM Na2HPC>4, 1 .93 mM NaH2PC>4, 0.5 mM EDTA, 0.01 % Nalsta, pH 7.6).
  • the MED15 KIX domain was expressed as a His6-GST fusion protein and purified by affinity chromatography with Ni-NTA resin (Qiagen) and size exclusion chromatography (Sephadex 75, Pharmacia).
  • the Kd for SREBP-1 a TAD binding to MED15 KIX was determined to be 36 nM and 2 mM with FITC and TAMRA tags, respectively, by fluorescence polarization (FP) assay.
  • the CBP KIX domain was expressed as GST fusion protein and purified by affinity chromatography with Pierce Glutathione Agarose resin (ThermoFisher) and size exclusion chromatography (Sephadex 75, Pharmacia).
  • the Kd for SREBP-1 a TAD binding to CBP KIX was determined to be 13 nM and 290 nM with FITC and TAMRA tags, respectively, by FP assay.
  • Round bottom 384-well assay plates (Corning cat. no. #3575) were used to prepare 30 pL samples with 30 nM SREBP-1 a FITC-peptide or 30 nM SREBP-1 a TAMRA-peptide.
  • GST-tagged MED15 KIX and CBP KIX were prepared with concentrations ranging from 0 to 300 mM.
  • Compound IC50s were determined with GST-tagged MED15 KIX and CBP KIX held at 3 pM and 1 pM, respectively. The peptide concentration was always kept at 30 nM regardless of the fluorophor.
  • Cells were seeded in 96 well plates as follows: U251 -MG cells were seeded in DMEM/F12 + 10% FBS at a density of 1 ,300 cells per well, RCC-JF cells were seeded in DMEM/F12 + 5% FBS at a density of 2,000 cells per well, and all other cell lines were plated to be in growth phase (-80% density) at the end of the assay. Cells were grown for - 24 hours before treatment. For 1 % LPDS (lipoprotein-deficient serum) treatment, media was removed and swapped with DMEM/F12 + 1 % LPDS. For full-serum treatment, media was not changed.
  • LPDS lipoprotein-deficient serum
  • U251 -MG cells were seeded in DMEM/F12 + 10% FBS in 96-well plates at a density of 5,000 cells per well and grown for 24 hours. Media was removed and swapped with DMEM/F12 + 1 % LPDS and SREBPi were added to indicated concentration. Cells were grown for 9 hours. After 9 hours, apoptosis was measured using a Caspase 3/7-Glo assay kit (Promega) and read with an Envision reader. Apoptosis was normalized to a DMSO vehicle control.
  • RCC-JF cells were seeded in 96-well plates in DMEM/F12 + 5% FBS to a density of 4,000 cells per well. After ⁇ 24h, cells were treated with SREBPi at concentrations indicated. After 24 hours, cell viability was measured using a CellTiter-Glo Luminescent Cell Viability Assay kit and apoptosis was measured using a Caspase 3/7-Glo assay kit (Promega). Plates were read with an Envision reader and values normalized to a DMSO vehicle control. The results of this assay are shown in FIGS. 15A and 15B.
  • DMEM/F12 + 5% FBS at a density of 100,000 cells per well. All other cells were seeded to be ⁇ 80% density at the end of the assay. After ⁇ 24 hours, media was removed, and cells were treated with SREBPi in DMEM/F12 + 1 % LPDS (for U251 -MG) or DMEM/F12 with no serum (RCC-JF) at a density of 100,000 cells per well. All other cells were seeded to be ⁇ 80% density at the end of the assay. After ⁇ 24 hours, media was removed, and cells were treated with SREBPi in DMEM/F12 + 1 % LPDS (for U251 -MG) or DMEM/F12 with no serum (RCC-JF) at
  • U251 -MG cells were seeded in DMEM/F12 + 10% FBS in 96 well plates at a density of 5,000 cells per well and grown overnight. Media was removed and swapped to DMEM/F12 + 1 % LPDS. Cells were transfected with siRNA using lipofectamine RNAiMAX. After 72 hours viability was assessed with a CellTiter-Glo Luminescent Cell Viability Assay kit (Promega) and apoptosis was measured using a Caspase 3/7-Glo assay kit (Promega); both were read with an Envision plate reader. cDNA was prepared for quantitative real-time PCR using a Cells-to-CT kit (Thermo Fisher). qRT-PCR reactions with FastStart Universal SYBR Green Master (ROX) (Roche) were run on a Roche LightCycler 480. Transcript abundance was normalized to RPLP0 and a non-targeting si control.
  • ROX FastStart Universal SYBR Green
  • U251 -MG cells were treated with SREBPi in DMEM/F12 + 1 % LPDS. After 20 hours, RNA was harvested using Qiagen RNeasy kit. cDNA made with Roche First Strand cDNA synthesis kit;
  • FIGS. 9A, 9B, 10A, and 10B The results of this assay are shown in FIGS. 9A, 9B, 10A, and 10B.
  • FASN-Luc a !uciferase-expressing vector containing a firefly luciferase open reading frame under the control of a minimal human fatty acid synthetase (FASN) promoter was used. Similar constructs under minimal promoters for CREB, LDLT, and SCD1 were used to test select compounds.
  • Duplicate 96-well plates (S!gma-A!drieh Cat No. P8616) were seeded at a density of 2.0x10 3 HepG2 cells per well. One of the seeded plates was transfected with FASN-Luc using
  • Lipofectamine® 2000 (Invitrogen Cat No. 1 1668) 9-12 hours post-seeding and media on the plate was changed from Opti-MEM® (Invitrogen Cat No. 31985) back to 10% fetal bovine serum supplemented Dulbecco's modified Eag!e medium (DMEM; Invitrogen Cat No. 10566) approximately 6 hours post transfection.
  • DMEM Dulbecco's modified Eag!e medium
  • compounds were added to both 96-well plates using identical plate layouts at select concentrations in triplicate in a total volume of 75 pL of DMEM with 1 % lipid- depleted serum per well.
  • RCC cells were seeded in 5% FBS to the following densities: RCC-AB 5000 cells/well, RCC-FG2 5000 cells per well, RCC-JF 3750 cells per well.
  • RCC-AB / P32 results are in FIGS. 16A and 16B.
  • RCC- FG2 / P32 results are in FIGS. 17A and 17B.
  • RCC-JF / P32 results are in FIGS. 18A and 18B.
  • RCC-AB / X1 results are in FIGS. 19A and 19B.
  • RCC-FG2 / X1 results are in FIGS. 20A and 20B.
  • RCC-JF / X1 results are in FIGS. 21 A and 21 B.
  • the results for erastin/P32 combination produced a synergy score of 32.34 and most synergistic area score of 38.73.
  • the data were generated using Bliss method. The results are shown in FIGS. 22A-22C.
  • FIG. 24A is a chart assessing the synergy between 666-15 and P32 in FBS, max score was 18.8.
  • FIG. 24B is a chart assessing the synergy between 666-15 and P32 in LPDS, max score was 6.2.
  • FIG. 25A is a chart assessing the synergy between fatostatin and P32 in FBS, max score was 12,34.
  • FIG. 24A is a chart assessing the synergy between 666-15 and P32 in FBS, max score was 18.8.
  • FIG. 24B is a chart assessing the synergy between 666-15 and P32 in LPDS, max score was 6.2.
  • FIG. 25A is a chart assessing the synergy between fatostatin and P32 in FBS, max score was 12,34.
  • 25B is a chart assessing the synergy between fatostatin and P32 in LPDS, max score was 5.88.
  • 26A is a chart assessing the synergy between A-485 and P32 in FBS, max score was 10.4.
  • FIG. 26B is a chart assessing the synergy between A-485 and P32 in LPDS, max score was 8.52.
  • FIG. 27A is a chart assessing the synergy between PF429242 and P32 in FBS, max score was 2.66.
  • FIG. 27B is a chart assessing the synergy between PF429242 and P32 in LPDS, max score was 3.04.
  • FIG. 28A is a chart assessing the synergy between 666-15 and X1 in FBS, max score was 13.2.
  • FIG. 28B is a chart assessing the synergy between 666-15 and X1 in LPDS, max score was 4.05.
  • FIG. 29A is a chart assessing the synergy between fatostatin and X1 in FBS, max score was 1 1 .83.
  • FIG. 29B is a chart assessing the synergy between fatostatin and X1 in LPDS, max score was 13.37.
  • FIG. 30A is a chart assessing the synergy between A-485 and X1 in FBS, max score was 2.56.
  • FIG. 30B is a chart assessing the synergy between A-485 and X1 in LPDS, max score was 0.98.
  • FIG. 31 A is a chart assessing the synergy between PF429242 and X1 in FBS, max score was 1 .067.
  • FIG. 31 B is a chart assessing the synergy between PF429242 and X1 in LPDS, max score was 4.64.
  • the compounds have the following structures:
  • ChIP was performed as described previously (Schmidt et al. , D. Schmidt, M.D. Wilson, C.
  • Primer sets used in the assay are as follows: FASN promoter: Fw: 5’- CCAAGCTGTCAGCCCATGT-3’ Rv: 5’- CGTCTCTCTGGCTCCCTCTA-3’, SCD promoter: Fw: 5’- GGCAGAGGGAACAGCAG ATT -3’ Rv: 5’- GGCTTCTGTAAACTCCGGCT-3’, HMGCR promoter: Fw: 5’- TCGAACGGCTATTGGTTGGC-3’ Rv: 5’- ACGAACGGTCGCCTTAACAA-3’. The results are shown in FIGS. 33 and 34.

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Abstract

L'invention concerne des agents capables de se lier au domaine KIX de CBP ou MED15 pour inhiber la liaison entre SREBP1 et le domaine KIX de MED15 ou CBP. L'invention concerne également des compositions contenant les agents et des procédés d'utilisation de celles-ci.
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WO2022120197A1 (fr) * 2020-12-03 2022-06-09 Emory University Associations d'inhibiteurs du récepteur du facteur de croissance épidermique et d'inhibiteurs de protéines de liaison à un élément régulateur de stérols destinées à être utilisées dans des thérapies anticancéreuses
WO2023081441A1 (fr) * 2021-11-08 2023-05-11 Ventus Therapeutics U.S., Inc. Composés hétérocycliques et leurs utilisations

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* Cited by examiner, † Cited by third party
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WO2022120197A1 (fr) * 2020-12-03 2022-06-09 Emory University Associations d'inhibiteurs du récepteur du facteur de croissance épidermique et d'inhibiteurs de protéines de liaison à un élément régulateur de stérols destinées à être utilisées dans des thérapies anticancéreuses
WO2023081441A1 (fr) * 2021-11-08 2023-05-11 Ventus Therapeutics U.S., Inc. Composés hétérocycliques et leurs utilisations

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