WO2013086002A1 - Compositions, process of preparation of said compositions and method of treating cancer - Google Patents

Compositions, process of preparation of said compositions and method of treating cancer Download PDF

Info

Publication number
WO2013086002A1
WO2013086002A1 PCT/US2012/067956 US2012067956W WO2013086002A1 WO 2013086002 A1 WO2013086002 A1 WO 2013086002A1 US 2012067956 W US2012067956 W US 2012067956W WO 2013086002 A1 WO2013086002 A1 WO 2013086002A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
aryl
independently
group
arylalkyl
Prior art date
Application number
PCT/US2012/067956
Other languages
French (fr)
Inventor
Shireen VALI
Shweta KAPOOR
Anay TALAWADEKAR
Zeba SULTANA
Ansu KUMAR
Pradeep Fernandes
Taher ABBASI
Original Assignee
Cellworks Research India Private Limited
Cellworks Group, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cellworks Research India Private Limited, Cellworks Group, Inc. filed Critical Cellworks Research India Private Limited
Publication of WO2013086002A1 publication Critical patent/WO2013086002A1/en

Links

Classifications

    • 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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • Embodiments of the disclosure describe compositions and kits, each containing compounds for use in the treatment of cancer, and associated therapies.
  • the disclosure also provides processes for obtaining the compositions and methods of treatment by administration of the compositions.
  • Cancer is a group of more than 100 diseases characterized by uncontrolled cell proliferation, and the acquisition of the ability to migrate, and invade, tissues and organs within different sites of the body by transformed cells. Although cancer can arise in virtually any of the body's tissues, each type of cancer has unique features. The basic processes that produce cancer are quite similar in all forms of the disease.
  • Cancer can be broadly classified into different categories.
  • Carcinomas are characterized by tumors, or cell masses, that reside within internal and external parts of the body such as the lung, breast, and colon.
  • Sarcomas are characterized by tumors that reside within bone, cartilage, fat, connective tissue, muscle, and other supportive tissues.
  • Lymphomas are cancers that begin in the lymph nodes and immune system tissues.
  • Leukemias are cancers that begin in the bone marrow and often mobilize into the bloodstream.
  • Adenomas are cancers that arise in the thyroid, the pituitary gland, the adrenal gland, and other glandular tissues.
  • Most cancers are characterized by de-regulation of multiple signaling pathways, and loss of cross-talk between them.
  • a cell breaks free from the normal restraints on cell division, and begins to follow its own agenda for proliferation, a mass of cells, or a tumor, produced by the division of this first, ancestral cell, will arise.
  • the progeny of the founder cell(s) will display the same inappropriate proliferation pattern(s), and the abnormal cell population will either remain within the tissue in which it originated, or they will begin to invade nearby tissues. The invasion of nearby tissues is known as metastasis.
  • An invasive, or metastatic, tumor is said to be malignant.
  • Metastatic cells can establish new tumors (metastases) elsewhere in the body. When mutations within a cancerous cell render the cell unable to stop uncontrolled division, growth, and tissue invasion, malignant tumors thrive. Mutations that inhibit tumor suppressor genes, suicide, and activate oncogene function, thereby not allowing cell(s) to regulate the cell machinery, result in unchecked division of cells, and the formation of tumors.
  • the invention provides a composition comprising: a) i) an AMPK activator; and ii) an inhibitor of P38-MAPK activity; and b) a pharmaceutically-acceptable excipient, wherein the composition is a unit dosage form.
  • the invention provides a kit comprising: a) i) an AMPK activator; and ii) an inhibitor of P38-MAPK activity; and b) written instructions on use of the kit.
  • the invention provides a method for treating a cancer in a subject in need or want of relief thereof, the method comprising administering to the subject: i) a therapeutically-effective amount of an AMPK activator; and ii) a therapeutically-effective amount of an inhibitor of P38-MAPK activity.
  • Figure 1 illustrates schematics of scientific rationale.
  • Figure 2 illustrates the dose response effect for CW178 across the selected tumor profiles.
  • Figure 3 illustrates the dose response effect for CW229 across the selected tumor profiles.
  • Figure 4a illustrates the efficacy of individual drugs CW178 and CW229, and the efficacy of combination drug CWG89in terms of Viability on H1299.
  • Figure 4b illustrates the efficacy of individual drugs CW178 and CW229, and the efficacy of combination drug CWG89 in terms of Viability on HCT116.
  • Figure 4c illustrates the efficacy of individual drugs CW178 and CW229, and the efficacy of combination drug CWG89in terms of Viability on MDA-MB-231.
  • Figure 5a illustrates the effect of individual drugs CW178 and CW229 and the combination CWG89 on phosphorylated AKT in selected tumor profiles
  • Figure 5b illustrates the effect of individual drugs CW178 and CW229 and the combination CWG89 on BAX dimers in selected tumor profiles
  • Figure 5c illustrates the effect of individual drugs CW178 and CW229 and the combination CWG89 on CDK4-CCND1 complex in selected tumor profiles
  • Figure 5d illustrates the effect of individual drugs CW178 and CW229 and the combination CWG89 on VEGFA levels in selected tumor profiles
  • Figure 6 illustrates the comparison of the efficacy of combination of the compounds on clinical parameter of viability with Erlotinib.
  • Erlotnib (TARCEVA®)
  • TARCEVA® is approved and is currently a market leader.
  • Figure 7 illustrates the dose response effect for CW178 on viability of NCI-H1299 cells.
  • Figure 8 illustrates the dose response effect for CW178 on viability of HCTl 16 cells.
  • Figure 9 illustrates the dose response effect for CW178 on viability of MDAMB231 cells.
  • Figure 10 illustrates the dose response effect for CW229 on viability of H1299 cells.
  • Figure 11 illustrates the dose response effect for CW229 on viability of HCTl 16 cells.
  • Figure 12 illustrates the dose response effect for CW229 on viability of MDAMB231 cells.
  • Figure 13 illustrates the effect of the combination of two drugs CWG89 on H1299 cells at low and high dosage.
  • Figure 14 illustrates the effect of the combination of two drugs CWG89 on HCTl 16 cells at low and high dosage.
  • Figure 15 illustrates the effect of the combination of two drugs CWG89 on MDAMB231 cells at low and high dosage.
  • Figure 16 illustrates the comparison of the individual effect of CW178 with the combination of two drugs CWG89 on H1299-virtual baseline.
  • Figure 17 illustrates the comparison of the individual effect of CW178 with the combination of two drugs CWG89 on HI 299 cells.
  • Figure 18 illustrates the comparison of the individual effect of CW229 with the combination of two drugs CWG89 on H1299-virtual baseline.
  • Figure 19 illustrates the comparison of the individual effect of CW229 with the combination of two drugs CWG89 on HI 299 cells.
  • Figure 20 illustrates the comparison of the individual effect of CW178 with the combination of two drugs CWG89 on HCT116-virtual baseline.
  • Figure 21 illustrates the comparison of the individual effect of CW178 with the combination of two drugs CWG89 on HCT116 cells.
  • Figure 22 illustrates the comparison of the individual effect of CW229 with the combination of two drugs CWG89 on HCT116-virtual baseline.
  • Figure 23 illustrates the comparison of the individual effect of CW229 with the combination of two drugs CWG89 on HCT116 cells.
  • Figure 24 illustrates the comparison of the individual effect of CW178 with the combination of two drugs CWG89 on MDAMB231 -virtual baseline.
  • Figure 25 illustrates the comparison of the individual effect of CW178 with the combination of two drugs CWG89 on MDAMB231 cells.
  • Figure 26 illustrates the comparison of the individual effect of CW229 with the combination of two drugs CWG89 on MDAMB231 -virtual baseline.
  • Figure 27 illustrates the comparison of the individual effect of CW229 with the combination of two drugs CWG89 on MDAMB231 cells.
  • Treatment of carcinomas can involve surgery, systemic therapy, therapies in
  • interventional radiology chemotherapy, radiation therapy, and/or immunotherapy.
  • Some patients can pursue one or more of these therapies in the management of their disease.
  • These therapies can remove or destroy cancer in a particular area of the body, yet they involve expensive, and painful, procedures that are not always effective.
  • NSCLC non-small cell lung cancer
  • colorectal cancers can be insensitive to conventional chemotherapy, radiation, and/or other standard-of-care treatments. In many diagnoses of early-stage carcinomas, surgery is often chosen as the treatment of choice if diagnosed at an early stage.
  • Available standard chemotherapy regimens targeting NSCLC include platinum-based therapies, such as cisp latin, vinca alkaloids, and/or a combination of both.
  • Platinum based therapies as exemplified by cisplatin, inhibit DNA repair and/or DNA synthesis in cancer cells by cross-linking DNA.
  • Vinca alkaloids target cancerous cells by destroying cellular structures necessary for cell growth, the mitotic spindles.
  • the combination of chemotherapies with different mechanisms of action, such as platinum and Paclitaxel, which inhibits cell division by binding to mitotic spindles rather than destroying them like vinca alkaloids do, modestly improves tumor response, and consequently survival, in NSCLC.
  • the 5-year survival rate for NSCLC patients can be approximately 15%.
  • NSCLC NSCLC
  • cetuximab is available for treatment of colorectal cancers.
  • Erlotinib is available for treating NSCLC. Although these can be useful in treating aspects of the disease, the drugs must be administered in a pre-specified sequence or in combination with other drugs.
  • chemotherapeutic drugs are associated with side effects of fatigue, diarrhea, mouth sores, nausea and vomiting, decreased white blood count with increased risk of infection, decreased platelet count with increased risk of bleeding, decreased red blood count with increased risk of tiredness, and numbness of hand and feet.
  • the overall quality of life of a patient undergoing cancer treatment with standard chemotherapy regimens is
  • the invention described herein provides an alternative to currently available therapies for the treatment of cancer.
  • the invention considered treatment of cancers where other available single agent therapies, or combinations of single agent therapies, have not been successful at simultaneously treating the disease, and improving one or more undesirable symptoms associated with the disease states or treatment.
  • the invention intervenes in the biochemical dynamics of both lung and colorectal cancer, and constitutes a therapy designed to target viability and proliferation cellular pathways within cells.
  • the invention intervenes in biochemical pathways associated with KRAS and/or BRAF mutations in tumor cells associated with KRAS and/or BRAF mutations. In some embodiments, such a tumor cell exhibits a mutation in each of KRAS and BRAF.
  • the disclosure provides a two-drug combination, which provides multi-targeted combination therapeutic approach to suppress and cure symptoms associated with cancer and associated conditions.
  • the drug combinations were designed using virtual co-culture computational simulations as described herein. Simulations performed with each individual drug were validated in aligned tumor cell line profiles, and provided more than 50% marker trend correlation as described herein.
  • the two-drug combination comprises a AMPK activator and a P38-MAPK inhibitor.
  • the two-drug combinations provide synergistic efficacy on the end-point markers, while dosing can be as low as, for example, the IC30 value of the drug.
  • Using a lower dose of the individual drug can provide an advantage in terms of minimizing the intensity of side-effects or toxicities associated with higher doses of the individual drugs.
  • the drug combination can inhibit multiple targets with low individual drug doses, so that an amplified effect can be observed on some or all of the primary end-point markers. Additionally, the low dosage drug combination can ensure that all the primary drug targets have some level of typical,
  • the invention disclosed herein provides a combination of two classes of drugs, which exhibit converging antagonistic effects on major oncogenic transcription factors through different mechanisms of action. Inhibition of transcription factors such as HIF1 A, NFkB and API can cause a systemic reduction in the expression and/or activity of oncogenic kinases and growth factors that are involved in tumor disease physiology, and tumor progression.
  • the drug combination targets multiple cell types in the micro environment including the angiogenic endothelial cell, the stromal fibroblast cell, and also impacts tumor mediated inflammation.
  • the inhibition of multiple pathways in multiple cell types provides a much needed multi-prong therapeutic effect, at low drug concentrations.
  • the drug combinations provided herein are effective in EGFR-resistive systems (anti- EGFR non-responders), because the two drug compounds affect diverse (EGFR-independent) strategic signaling points distributed across two distinct pathways in the relevant cell systems. This phenomenon allows even minor inhibitory effects from each strategic point to produce an enhanced inhibitory effect upon convergence of the minor effects, thereby amplifying the effect on the pool of biomarkers.
  • the invention provides a composition comprising: a) i) an AMPK activator; and ii) an inhibitor of P38-MAPK activity; and b) a pharmaceutically-acceptable excipient, wherein the composition is a unit dosage form.
  • the invention provides a kit comprising: a) i) an AMPK activator; and ii) an inhibitor of P38-MAPK activity; and b) written instructions on use of the kit.
  • the CW178 class of drugs functions by activating AMPK.
  • the CW229 class of drugs can inhibit the enzyme P38-MAPK activity and can induce anti-pro liferative effects.
  • CW229 is an inhibitor of P38.
  • CWG89 refers to a combination of any CW178 compound, and any CW229 compound in any amount, ratio, concentration, or order thereof.
  • Non- limiting examples of CW178 include: a) Metformin, also known as 1,1- dimethylbiguanide, N,N-dimethyldiguanide, N'-dimethylguanylguanidine, and DMGG, or a pharmaceutically-acceptable salt thereof, such as Embonate, Hydrochloride, and/or p- Chlorophenoxyacetate salts; b) Phenformin, also known as 1-phenethylbiguanide,
  • phenethyldiguanide ⁇ '- ⁇ -phenethylformamidinyliminourea, fenformin, fenormin, ⁇ -PEBG, PEDG, or a pharmaceutically-acceptable salt thereof, such as a hydrochloride salt
  • Panduratin also known as (2,6-dihydroxy-4-methoxyphenyl)-[(lR,2S,6R)-3-methyl-2-(3-methylbut-2-enyl)- 6-phenylcyclohex-3-en-l-yl]methanone, or a pharmaceutically-acceptable salt thereof
  • AICAPv also known as [(2R,3S,4R,5R)-5-(5-amino-4-carbamoylimidazol-l-yl)-3,4- dihydroxyoxolan-2-yl]methyl dihydrogen phosphate, or a pharmaceutically-acceptable salt thereof
  • CID 16760291 CID 16760291
  • Non-limiting examples of CW178 include the compounds of Table 1.
  • Table 1 Examples of CW178 compounds.
  • the invention provides a compound of Formula (I):
  • each of R 1 , R 2 , R 3 , R 4 , and R 5 is independently H, OH, SH, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, or alkylheterocyclyl, wherein each alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, and alkylheterocyclyl group is independently unsubstituted or substituted, or any two of R 1 , R 2 , R 3 , R 4 , and R 5 form a ring together with the atoms to which they are bound, wherein the ring is unsubstituted or substituted; each of X and Y is independently O, S, C(R 6 )(R 7 ), N + (R 6 )(R 7 ), or N(R 6 );
  • R 6 and R 7 form a ring with the atoms to which they are bound, wherein the ring is unsubstituted or substituted, or a pharmaceutically-acceptable salt thereof.
  • R 1 and R 2 form a ring with the atoms to which they are bound.
  • R 1 and R 3 form a ring with the atoms to which they are bound.
  • R 2 and R 3 form a ring with the atoms to which they are bound.
  • R 3 and R 4 form a ring with the atoms to which they are bound.
  • R 3 and R 5 form a ring with the atoms to which they are bound.
  • R 4 and R 5 form a ring with the atoms to which they are bound.
  • one or both of X and Y are N(R 6 ). In some embodiments, both of X and Y are N(R 6 ). In some embodiments, R 6 is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, or alkylheterocyclyl, wherein each alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, and alkylheterocyclyl group is independently unsubstituted or substituted.
  • R 6 is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, or alkylheterocyclyl. In some embodiments, R 6 is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, or alkylaryl. In some
  • R 6 is H, alkyl, or aryl. In some embodiments, R 6 is H.
  • each of R 1 , R 2 , R 3 , R 4 , and R 5 is independently H, alkyl, alkenyl, aryl, arylalkyl, or alkylaryl, wherein each alkyl, alkenyl, aryl, arylalkyl, and alkylaryl group is independently unsubstituted or substituted;
  • each of X and Y is independently N(R 6 ); and each R 6 is independently H, alkyl, alkenyl, aryl, arylalkyl, or alkylaryl, wherein each alkyl, alkenyl, aryl, arylalkyl, and alkylaryl, group is independently unsubstituted or substituted.
  • each of R 1 , R 2 , R 3 , R 4 , and R 5 is independently H, alkyl, alkenyl, aryl, arylalkyl, or alkylaryl, wherein each alkyl, alkenyl, aryl, arylalkyl, and alkylaryl group is independently unsubstituted or substituted; each of X and Y is independently N(R 6 ); and each R 6 is independently H, alkyl, or arylalkyl, wherein each alkyl, alkenyl, aryl, arylalkyl, and alkylaryl, group is independently unsubstituted or substituted.
  • each of R 1 , R 2 , R 3 , R 4 , and R 5 is independently H, alkyl, or arylalkyl; each of X and Y is independently N(R 6 ); and each R 6 is independently H or alkyl.
  • each of R 1 , R 2 and R 3 is H; each of R 4 and R 5 is alkyl; each of X and Y is N(R 6 ); and each R 6 is H.
  • each of R 1 , R 2 and R 3 is H; each of R 4 and R 5 is independently methyl, ethyl, propyl, or isopropyl; each of X and Y is independently N(R 6 ); and each R 6 is H.
  • each of R 1 , R 2 and R 3 is H; each of R 4 and R 5 is methyl; each of X and Y is N(R 6 ); and each R 6 is H.
  • each of R 1 , R 2 , R 3 , and R 4 is H; R 5 is arylalkyl; each of X and Y is N(R 6 ); and each R 6 is H.
  • each of R 1 , R 2 , R 3 , and R 4 is H;
  • R 5 is an arylalkyl group of the formula: Ar-(CH 2 ) n - , wherein Ar is aryl, and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each of X and Y is N(R 6 ); and each R 6 is H.
  • each of R 1 , R 2 , R 3 , and R 4 is H;
  • R 5 is an arylalkyl group of the formula: Ar-(CH 2 ) n - , wherein Ar is aryl, and n is 1, 2, or 3; each of X and Y is N(R 6 ); and each
  • R 6 is H.
  • each of R 1 , R 2 , R 3 , and R 4 is H;
  • R 5 is an arylalkyl group of the formula: Ar-(CH 2 ) n - , wherein Ar is phenyl, and n is 1, 2, or 3;
  • each of X and Y is N(R 6 ); and each R 6 is H.
  • each of R 1 , R 2 , R 3 , and R 4 is H;
  • R 5 is an arylalkyl group of the formula: Ar-(CH 2 ) n - , wherein Ar is phenyl, and n is 1 ;
  • each of X and Y is N(R 6 ); and each R 6 is H.
  • each of R 1 , R 2 , R 3 , and R 4 is H;
  • R 5 is an arylalkyl group of the formula: Ar-(CH 2 ) n - , wherein Ar is phenyl, and n is 2;
  • each of X and Y is N(R 6 ); and each R 6 is H.
  • the compound of Formula (I) is a compound of Formula (II):
  • the compound of Formula (I) is:
  • the compound of Formula (I) is:
  • the compound of Formula (I) is metformin.
  • the compound of Formula (I) is phenformin.
  • CW229 include: a) RWJ67657, also known as 4-[4-(4- fluorophenyl)- 1 -(3-phenylpropyl)-5-pyridin-4-ylimidazol-2-yl]but-3-yn- 1 -ol or a
  • ARRY-797 also known as (4-difluorophenoxy)-N- [2-(dimethylamino)ethyl]-l-(2-methylpropyl) indazole-6-carboxamide, or a pharmaceutically- acceptable salt thereof
  • SB203580 also known as 4-[4-(4-fluorophenyl)-2-(4- methylsulfinylphenyl)-lH-imidazol-5-yl] pyridine, or a pharmaceutically-acceptable salt thereof
  • PH-797804 also known as 3-[3-bromo-4-[(2,4-difluorophenyl)methoxy]-6-methyl-2- oxopyridin-l-yl]-N,4-dimethylbenzamide, or a pharmaceutically-acceptable salt thereof
  • SB220025 also known as 4-[5-(4-fluorophenyl)-3-piperidin-4-ylimidazol-4-yl]pyrimidin-2- amine, or a pharmaceutically-acceptable salt thereof
  • SB202190 also known as 4-[4-(4- fluorophenyl)-5-pyridin-4-yl- 1 ,3-dihydroimidazol-2-ylidene]cyclohexa-2,5-dien- 1 -one, or a pharmaceutically-acceptable salt thereof
  • SB239063 also known as 4-[4-(4-fluorophenyl)-5- (2-methoxypyrimidin-4-yl)imidazol-l-yl]cyclohexan-l-ol, or a pharmaceutically-acceptable salt thereof
  • SB242235 also known as 4-[5-(4-fluorophenyl)-3-piperidin-4-ylimidazol-4-yl
  • CHEMBL512255 also known as 3-[6-(2,4-difluoroanilino)-2H-pyrazolo[3,4-b]pyridin-3-yl]-4- methoxy-N-morpholin-4-ylbenzamide, or a pharmaceutically-acceptable salt thereof;
  • LY- 2228820 also known as 5-[2-tert-butyl-4-(4-fluorophenyl)-lH-imidazol-5-yl]-3-(2,2- dimethylpropyl)imidazo[4,5-b]pyridin-2-amine, or a pharmaceutically-acceptable salt thereof such as a methanesulfonic acid salt;
  • ML3403 also known as 4-[5-(4-fluorophenyl)-2- methylsulfanyl-lH-imidazol-4-yl]-N-(l-phenylethyl)pyridin-2-amine), or a pharmaceutically- acceptable salt thereof.
  • the invention provides a compound of Formula (III):
  • Z is O, S, or N(R 10 ); each of R 8 , R 9 , R 10 , and R 11 is independently H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, or alkylheterocyclyl, wherein each alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, and alkylheterocyclyl group is independently unsubstituted or substituted, or any two of R 8 , R 9 , R 10 , and R 11 form a ring together with the atoms to which they are bound, wherein the ring is unsubstituted or substituted, or a pharmaceutically-acceptable salt or tautomer thereof.
  • Z is N(R 10 ).
  • the compound of Formula (III) is a compound of Formula (IV):
  • each of R 8 , R 9 , R 10 , and R 11 is independently H, alkyl, alkenyl, alkynyl, alkoxy, thioether, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, or alkylheterocyclyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, thioether, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, and alkylheterocyclyl group is independently unsubstituted or substituted, or any two of R 8 , R 9 , R 10 , and R 11 form a ring together with the atoms to which they are bound, wherein the ring is unsubstituted or substituted.
  • R 8 is H, alkyl, aryl or heterocyclyl. In some embodiments, R 8 is aryl or heterocyclyl.
  • R 8 is:
  • each R 12 is independently H, OH, SH, F, CI, Br, I, amino, mono-substituted amino, di- substituted amino, alkyl, alkoxy, thioether, a carboxylic acid group, an ester group, an amido group, or a carbamoyl group.
  • R 8 is: wherein R 12 is H, OH, SH, F, CI, Br, I, amino, mono-substituted amino, di-substituted amino, alkyl, alkoxy, thioether, a carboxylic acid group, an ester group, an amido group, or a carbamoyl group.
  • R 12 can be in the ortho, meta, or para position.
  • R 8 is:
  • R 12 is H, OH, SH, F, CI, Br, I, amino, mono-substituted amino, di-substituted amino, alkyl, alkoxy, thioether, a carboxylic acid group, an ester group, an amido group, or a carbamoyl group.
  • R 12 is H, OH, SH, F, CI, Br, I, amino, mono-substituted amino, or di-substituted amino. In some embodiments, R 12 is H, F, CI, Br, or I. In some embodiments, R 12 is F, CI, Br, or I. In some embodiments, R 12 is F. In some embodiments, R 12 is CI. In some embodiments, R 12 is Br. In some embodiments, R 12 is I.
  • R 9 is H, alkyl, aryl or heterocyclyl. In some embodiments,
  • R 9 is aryl or heterocyclyl.
  • R 9 is:
  • R is:
  • each R 13 is independently H, amino, mono-substituted
  • R 9 is:
  • each R 13 is independently H, amino, mono-substituted amino, or di-substituted amino.
  • R 9 is:
  • R 13 is H, amino, mono-substituted amino, or di-substituted ammo. [00107] In some embodiments, R 13 is H or mono-substituted amino. In some embodiments, R 13 is mono-substituted amino. In some embodiments, R 13 is arylalkyl
  • A is O, S, N, or N(R 15 );
  • B is O, S, N, or N(R 15 );
  • R 14 is H, OH, SH, amino, mono-substituted amino, or di-substituted amino; each R 15 is
  • R 9 is:
  • R 15 wherein R 14 is H, OH, SH, amino, mono-substituted or di-substituted amino; and R 15 is H or alkyl.
  • R 14 is amino.
  • R 15 is alkyl.
  • R 9 is:
  • R is:
  • R 16 is H, OH, SH, amino, mono-substituted amino, di-substituted amino, alkyl, or alkoxy.
  • R is:
  • R 16 is H, OH, SH, amino, mono-substituted amino, di-substituted amino, alkyl, or alkoxy.
  • R 16 is H, amino, or alkoxy.
  • R 10 is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, or alkylheterocyclyl, wherein each alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, and alkylheterocyclyl group is
  • R 10 is H, alkyl, arylalkyl, alkylaryl, or heterocyclyl.
  • R 10 is H
  • R 10 is an arylalkyl group of the formula: Ar-(CH 2 ) n - , wherein Ar is aryl, and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, Ar is phenyl, some embodiments, n is 1, 2, or 3.
  • R 10 is:
  • R 11 is thioether. In some embodiments, R 11 is SMe. [00122] In some embodiments, R 11 is alkyl. In some embodiments, R 11 is branched alkyl.
  • R 11 is t-butyl
  • R 11 is alkynyl. In some embodiments, R 11 is: , wherein p is 1, 2, 3, 4, or 5. In some embodiments, p is 1. In some embodiments, p is 2.
  • R 11 is aryl
  • R 11 is:
  • each R 17 is independently H, OH, SH, halogen, amino, mono- substituted amino, di-substituted amino, alkyl, aryl, heterocyclyl, an ester group, an alkoxy group, a thioether group, an amido group, a carbamate group, or S(0)CH 3 .
  • R 11 is:
  • R 17 is H, OH, SH, halogen, amino, mono-substituted amino, di-substituted amino, alkyl, aryl, heterocyclyl, an ester group, an alkoxy group, a thioether group, an amido group, a carbamate group, or S(0)CH 3 .
  • each R 17 is independently H, OH, or S(0)CH 3 .
  • the compound of Formula (III) is a compound of Formula
  • R 13 is as defined herein,
  • R 16 is as defined herein;
  • R 10 is: H, Ar-(CH 2 ) n - , wherein Ar is
  • phenyl and n is 1, 2, or 3, or ; and R 11 is: H, alkyl, or
  • R 17 is OH or S(0)CH 3 [00129] In some embodiments: hal is F; R is:
  • R 13 is as defined herein; R 10 is H; R 11 is: wherein
  • R 17 is OH or S(0)CH 3 .
  • R 13 is H and R 17 is OH.
  • Het is a heterocycle that is unsubstituted or substituted; and Aryl is an aryl group that is unsubstituted or substituted, or a pharmaceutically-acceptable salt thereof.
  • the compound of Formula (VI) is a compound of Formula
  • R 18 is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, or alkylheterocyclyl, wherein the alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, and alkylheterocyclyl group is unsubstituted or substituted; each of R 19 , R 20 , and R 21 is independently H, OH, SH, halogen, amino, mono-substituted amino, di- substituted amino, alkyl, aryl, heterocyclyl, an ester group, an alkoxy group, a thioether group, an amido group, or a carbamate group; p is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and q is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • p is 1, 2, or 3.
  • q is 1, 2, or 3.
  • p is 2.
  • q is 2.
  • the compound of Formula (VI) is a compound of Formula
  • R 18 is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, or alkylheterocyclyl, wherein the alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, and alkylheterocyclyl group is unsubstituted or substituted; and each of R 19 and R 20 is independently H, OH, SH, halogen, amino, mono-substituted amino, di- substituted amino, alkyl, aryl, heterocyclyl, an ester group, an alkoxy group, a thioether group, an amido group, or a carbamate group.
  • R 18 is H, alkyl, aryl, alkylaryl, or heterocyclyl. In some embodiments,
  • R is alkyl or alkylaryl. In some embodiments, each of R and R is independently H, OH, SH, halogen, an alkoxy group, or a thioether group. In some
  • each of R 19 and R 20 is independently an alkoxy group or a thioether group.
  • R 19 is an alkoxy group.
  • R 20 is a thioether group.
  • the compound of Formula (VI) is:
  • the compound of Formula (VI) is SB 681323.
  • optional substituents include hydroxyl groups, sulfhydryl groups, halogens, amino groups, nitro groups, nitroso groups, cyano groups, azido groups, sulfoxide groups, sulfone groups, sulfonamide groups, carboxyl groups, carboxaldehyde groups, imine groups, alkyl groups, halo-alkyl groups, alkenyl groups, halo-alkenyl groups, alkynyl groups, halo-alkynyl groups, alkoxy groups, aryl groups, aryloxy groups, aralkyl groups, arylalkoxy groups, heterocyclyl groups, acyl groups, acyloxy groups, carbamate groups, amide groups, urethane groups, and ester groups.
  • Non-limiting examples of alkyl groups include straight, branched, and cyclic alkyl groups.
  • Non-limiting examples of straight alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl.
  • Branched alkyl groups include any straight alkyl group substituted with any number of alkyl groups.
  • Non- limiting examples of branched alkyl groups include isopropyl, isobutyl, sec-butyl, and t-butyl.
  • Non-limiting examples of cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptlyl, and cyclooctyl groups. Cyclic alkyl groups also include fused-, bridged-, and spiro-bicycles and higher fused-, bridged-, and spiro-systems. A cyclic alkyl group can be substituted with any number of straight, branched, or cyclic alkyl groups.
  • Non-limiting examples of alkenyl groups include straight, branched, and cyclic alkenyl groups.
  • the olefin or olefins of an alkenyl group can be, for example, E, Z, cis, trans, terminal, or exo-methylene.
  • Non-limiting examples of alkynyl groups include straight, branched, and cyclic alkynyl groups.
  • the triple bond of an alkylnyl group can be internal or terminal.
  • a halo group can be any halogen atom, for example, fluorine, chlorine, bromine, or iodine.
  • a halo-alkyl group can be any alkyl group substituted with any number of halogen atoms, for example, fluorine, chlorine, bromine, and iodine atoms.
  • a halo-alkenyl group can be any alkenyl group substituted with any number of halogen atoms.
  • a halo-alkynyl group can be any alkynyl group substituted with any number of halogen atoms.
  • An alkoxy group can be, for example, an oxygen atom substituted with any alkyl, alkenyl, or alkynyl group.
  • An ether or an ether group comprises an alkoxy group.
  • alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, and isobutoxy.
  • An aryl group can be heterocyclic or non-heterocyclic.
  • An aryl group can be monocyclic or polycyclic.
  • An aryl group can be substituted with any number of substituents, for example, hydrocarbyl groups, alkyl groups, alkoxy groups, and halogen atoms.
  • Non-limiting examples of aryl groups include phenyl, toluyl, naphthyl, pyrrolyl, pyridyl, imidazolyl, thiophenyl, and furyl.
  • An aryloxy group can be, for example, an oxygen atom substituted with any aryl group, such as phenoxy.
  • An aralkyl group can be, for example, any alkyl group substituted with any aryl group, such as benzyl.
  • An arylalkoxy group can be, for example, an oxygen atom substituted with any aralkyl group, such as benzyloxy.
  • a heterocycle can be any ring containing a ring atom that is not carbon.
  • a heterocycle can be substituted with any number of substituents, for example, alkyl groups and halogen atoms.
  • a heterocycle can be aromatic or non-aromatic.
  • Non-limiting examples of heterocycles include pyrrole, pyrrolidine, pyridine, piperidine, succinamide, maleimide, morpholine, imidazole, thiophene, furan, tetrahydrofuran, pyran, and tetrahydropyran.
  • An acyl group can be, for example, a carbonyl group substituted with
  • acyl include acetyl, benzoyl, benzyloxycarbonyl, phenoxycarbonyl, methoxycarbonyl, and ethoxycarbonyl.
  • An acyloxy group can be an oxygen atom substituted with an acyl group.
  • An ester or an ester group comprises an acyloxy group.
  • a non- limiting example of an acyloxy group, or an ester group, is acetate.
  • a carbamate group can be an oxygen atom substituted with a carbamoyl group, wherein the nitrogen atom of the carbamoyl group is unsubstituted, mono substituted, or disubstituted with one or more of hydrocarbyl, alkyl, aryl, heterocyclyl, or aralkyl. When the nitrogen atom is disubstituted, the two substituents together with the nitrogen atom can form a heterocycle.
  • the disclosure provides the use of pharmaceutically-acceptable salts of any compound described herein. Pharmaceutically-acceptable salts include, for example, acid- addition salts and base-addition salts.
  • the acid that is added to the compound to form an acid- addition salt can be an organic acid or an inorganic acid.
  • a base that is added to the compound to form a base-addition salt can be an organic base or an inorganic base.
  • a pharmaceutically-acceptable salt is a metal salt.
  • a pharmaceutically- acceptable salt is an ammonium salt.
  • Metal salts can arise from the addition of an inorganic base to a compound of the disclosure.
  • the inorganic base consists of a metal cation paired with a basic counterion, such as, for example, hydroxide, carbonate, bicarbonate, or phosphate.
  • the metal can be an alkali metal, alkaline earth metal, transition metal, or main group metal.
  • the metal is lithium, sodium, potassium, cesium, cerium, magnesium, manganese, iron, calcium, strontium, cobalt, titanium, aluminum, copper, cadmium, or zinc.
  • a metal salt is a lithium salt, a sodium salt, a potassium salt, a cesium salt, a cerium salt, a magnesium salt, a manganese salt, a iron salt, a calcium salt, a strontium salt, a cobalt salt, a titanium salt, an aluminum salt, a copper salt, a cadmium salt, or a zinc salt.
  • Ammonium salts can arise from the addition of ammonia or an organic amine to a compound of the disclosure.
  • the organic amine is triethyl amine, diisopropyl amine, ethanol amine, diethanol amine, triethanol amine, morpholine, N- methylmorpholine, piperidine, N-methylpiperidine, N-ethylpiperidine, dibenzylamine, piperazine, pyridine, pyrrazole, pipyrrazole, imidazole, pyrazine, or pipyrazine.
  • an ammonium salt is a triethyl amine salt, a diisopropyl amine salt, an ethanol amine salt, a diethanol amine salt, a triethanol amine salt, a morpholine salt, an N-methylmorpholine salt, a piperidine salt, an N-methylpiperidine salt, an N- ethylpiperidine salt, a dibenzylamine salt, a piperazine salt, a pyridine salt, a pyrrazole salt, a pipyrrazole salt, an imidazole salt, a pyrazine salt, or a pipyrazine salt.
  • Acid addition salts can arise from the addition of an acid to a compound of the disclosure.
  • the acid is organic.
  • the acid is inorganic.
  • the acid is hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, nitrous acid, sulfuric acid, sulfurous acid, a phosphoric acid, isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbic acid, gentisinic acid, gluconic acid, glucaronic acid, saccaric acid, formic acid, benzoic acid, glutamic acid, pantothenic acid, acetic acid, propionic acid, butyric acid, fumaric acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, oxalic acid, or maleic acid.
  • the salt is a hydrochloride salt, a hydrobromide salt, a hydroiodide salt, a nitrate salt, a nitrite salt, a sulfate salt, a sulfite salt, a phosphate salt, isonicotinate salt, a lactate salt, a salicylate salt, a tartrate salt, an ascorbate salt, a gentisinate salt, a gluconate salt, a glucaronate salt, a saccarate salt, a formate salt, a benzoate salt, a glutamate salt, a pantothenate salt, an acetate salt, a propionate salt, a butyrate salt, a fumarate salt, a succinate salt, a methanesulfonate (mesylate) salt, an ethanesulfonate salt, a benzenesulfonate salt, a p-tolu
  • a pharmaceutical composition of the disclosure can be a combination of any pharmaceutical compounds described herein with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
  • the pharmaceutical composition facilitates administration of the compound to an organism.
  • Pharmaceutical compositions can be administered in therapeutically-effective amounts as pharmaceutical compositions by any form and route known in the art including, for example, intravenous, subcutaneous, intramuscular, oral, rectal, aerosol, parenteral, ophthalmic, pulmonary, transdermal, vaginal, otic, nasal, and topical administration.
  • a pharmaceutical composition can be administered in a local or systemic manner, for example, via injection of the compound directly into an organ, optionally in a depot or sustained release formulation.
  • Pharmaceutical compositions can be provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation.
  • a rapid release form can provide an immediate release.
  • An extended release formulation can provide a controlled release or a sustained delayed release.
  • compositions can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers or excipients well known in the art.
  • Such carriers can be used to formulate tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions and the like, for oral ingestion by a subject.
  • compositions for oral use can be obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Cores can be provided with suitable coatings.
  • concentrated sugar solutions can be used, which may optionally contain an excipient such as gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments can be added to the tablets or dragee coatings, for example, for identification or to characterize different combinations of active compound doses.
  • compositions which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the capsule comprises a hard gelatin capsule comprising one or more of pharmaceutical, bovine, and plant gelatins.
  • a gelatin can be alkaline processed.
  • the push- fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. Stabilizers can be added. All formulations for oral administration are provided in dosages suitable for such administration.
  • compositions can be tablets, lozenges, or gels.
  • Parental injections can be formulated for bolus injection or continuous infusion.
  • compositions can be in a form suitable for parenteral injection as a sterile suspension, solution or emulsion in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Suspensions of the active compounds can be prepared as oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions can contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension can also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the active ingredient can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen- free water, before use.
  • the active compounds can be administered topically and can be formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams, and ointments.
  • Such pharmaceutical compositions can contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
  • Formulations suitable for transdermal administration of the active compounds can employ transdermal delivery devices and transdermal delivery patches, and can be lipophilic emulsions or buffered aqueous solutions, dissolved and/or dispersed in a polymer or an adhesive. Such patches may be constructed for continuous, pulsatile, or on demand delivery of
  • Transdermal delivery can be accomplished by means of
  • transdermal patches can provide controlled delivery. The rate of absorption can be slowed by using rate-controlling membranes or by trapping the compound within a polymer matrix or gel.
  • absorption enhancers can be used to increase absorption.
  • An absorption enhancer or carrier can include absorbable pharmaceutically acceptable solvents to assist passage through the skin.
  • transdermal devices can be in the form of a bandage comprising a backing member, a reservoir containing compounds and carriers, a rate controlling barrier to deliver the compounds to the skin of the subject at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
  • the active compounds can be in a form as an aerosol, a mist, or a powder.
  • Pharmaceutical compositions are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane,
  • the dosage unit can be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator can be formulated containing a powder mix of the compounds and a suitable powder base such as lactose or starch.
  • the compounds can also be formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and the like.
  • rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas
  • conventional suppository bases such as cocoa butter or other glycerides
  • synthetic polymers such as polyvinylpyrrolidone, PEG, and the like.
  • a low-melting wax such as a mixture of fatty acid glycerides, optionally in combination with cocoa butter, is first melted.
  • therapeutically- effective amounts of the compounds described herein are administered in pharmaceutical compositions to a subject having a disease or condition to be treated.
  • the subject is a mammal such as a human.
  • a therapeutically-effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compounds used, and other factors.
  • the compounds can be used singly or in combination with one or more therapeutic agents as components of mixtures.
  • compositions can be formulated using one or more
  • physiologically-acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compounds into preparations that can be used pharmaceutically.
  • Formulation can be modified depending upon the route of administration chosen.
  • compositions comprising a compounds described herein can be manufactured in a conventional manner, for example, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.
  • the pharmaceutical compositions can include at least one pharmaceutically acceptable carrier, diluent, or excipient and compounds described herein as free-base or pharmaceutically-acceptable salt form.
  • the methods and pharmaceutical compositions described herein include the use crystalline forms (also known as polymorphs), and active metabolites of these compounds having the same type of activity.
  • compositions comprising the compounds described herein include formulating the compounds with one or more inert, pharmaceutically- acceptable excipients or carriers to form a solid, semi-solid, or liquid composition.
  • Solid compositions include, for example, powders, tablets, dispersible granules, capsules, cachets, and suppositories.
  • Liquid compositions include, for example, solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein.
  • Semi-solid compositions include, for example, gels, suspensions and creams.
  • compositions can be in liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions can also contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and other
  • Liposomes are composed of natural phospholipids, and can contain mixed lipid chains with surfactant properties (e.g., egg phosphatidylethanolamine).
  • a liposome design can employ surface ligands for attaching to unhealthy tissue.
  • Non-limiting examples of liposomes include the multilamellar vesicle (MLV), the small unilamellar vesicle (SUV), and the large unilamellar vesicle (LUV).
  • Liposomal physico chemical properties can be modulated to optimize penetration through biological barriers and retention at the site of administration, and to prevent premature degradation and toxicity to non-target tissues.
  • Optimal liposomal properties depend on the administration route: large-sized liposomes show good retention upon local injection, small-sized liposomes are better suited to achieve passive targeting.
  • PEGylation reduces the uptake of the liposomes by liver and spleen, and increases the circulation time, resulting in increased localization at the inflamed site due to the enhanced permeability and retention (EPR) effect.
  • liposomal surfaces can be modified to achieve selective delivery of the encapsulated drug to specific target cells.
  • Non- limiting examples of targeting ligands include monoclonal antibodies, vitamins, peptides, and polysaccharides specific for receptors concentrated on the surface of cells associated with the disease.
  • Non-limiting examples of dosage forms suitable for use in the disclosure include feed, food, pellet, lozenge, liquid, elixir, aerosol, inhalant, spray, powder, tablet, pill, capsule, gel, geltab, nanosuspension, nanoparticle, microgel, suppository troches, aqueous or oily suspensions, ointment, patch, lotion, dentifrice, emulsion, creams, drops, dispersible powders or granules, emulsion in hard or soft gel capsules, syrups, phytoceuticals, nutraceuticals, and any combination thereof.
  • Non-limiting examples of pharmaceutically-acceptable excipients suitable for use in the disclosure include granulating agents, binding agents, lubricating agents, disintegrating agents, sweetening agents, glidants, anti-adherents, anti-static agents, surfactants, anti-oxidants, gums, coating agents, coloring agents, flavouring agents, coating agents, plasticizers, preservatives, suspending agents, emulsifying agents, plant cellulosic material and
  • a composition of the disclosure can be, for example, an immediate release form or a controlled release formulation.
  • An immediate release formulation can be formulated to allow the compounds to act rapidly.
  • Non-limiting examples of immediate release formulations include readily dissolvable formulations.
  • a controlled release formulation can be a pharmaceutical formulation that has been adapted such that drug release rates and drug release profiles can be matched to physiological and chronotherapeutic requirements or, alternatively, has been formulated to effect release of a drug at a programmed rate.
  • Non-limiting examples of controlled release formulations include granules, delayed release granules, hydrogels (e.g., of synthetic or natural origin), other gelling agents (e.g., gel-forming dietary fibers), matrix-based formulations (e.g., formulations comprising a polymeric material having at least one active ingredient dispersed through), granules within a matrix, polymeric mixtures, granular masses, and the like.
  • compositions of the disclosure can be delivered via a time-controlled delivery system.
  • a time-controlled delivery system is the PULSINCAP® system, or a variant thereof.
  • the time-controlled delivery system can further comprise pH-dependent systems, microbially-triggered delivery systems, or a combination thereof.
  • the time-controlled system may comprise a water insoluble capsule body enclosing a drug reservoir.
  • the capsule body can be closed at one end with a hydrogel plug.
  • the hydrogel plug can comprise swellable polymers, erodible compressed polymers, congealed melted polymers, enzymatically-controlled erodible polymers, or a combination thereof.
  • the swellable polymers can include
  • Non-limiting examples of erodible compressed polymers include hydroxypropyl methylcellulose, polyvinyl alcohol, polyvinyl acetate, polyethylene oxide, and combinations thereof.
  • Non-limiting examples of congealed melted polymers include saturated polyglycolated glycerides, glyceryl monooleate, and combinations thereof.
  • Non-limiting examples of enzymatically-controlled erodible polymers include polysaccharides; amylose; guar gum; pectin; chitosan; inulin; cyclodextrin; chondroitin sulphate; dextrans; locust bean gum; arabinogalactan; chondroitin sulfate; xylan; calcium pectinate; pectin/chitosan mixtures;
  • amidated pectin and combinations thereof.
  • the time-controlled delivery system can comprise a capsule, which further comprises an organic acid.
  • the organic acid can be filled into the body of a hard gelatine capsule.
  • the capsule can be coated with multiple layers of polymers.
  • the capsule can be coated first with an acid soluble polymer, such as EUDRAGIT® E, then with a hydrophilic polymer, such as hydroxypropyl methylcellulose, and finally with an enteric coating, such as
  • CHRONOTROPIC® system or a variant thereof, which comprises a drug core that is coated with hydroxypropyl methylcellulose and an outer enteric film.
  • the time-controlled delivery system can comprise a capsule body, which can house, for example, a drug-containing tablet, an erodible tablet, a swelling expulsion excipient, or any combination thereof.
  • the capsule can comprise an ethyl cellulose coat.
  • the time-controlled delivery system can comprise two different sized capsules, one inside the other. The space between the capsules can comprise a hydrophilic polymer.
  • the drug-containing core canay be housed within the inner capsule.
  • the drug delivery system can comprise an impermeable shell, a drug-containing core, and erodible outer layers at each open end. When the outer layers erode, the drug is released.
  • Examples of suitable multiparticulate drug delivery systems include
  • the drug delivery system can comprise multiparticulate beads, which are comprised of multiple layers of the drug compound, excipients, and release-controlling polymers.
  • the multiparticulate beads can comprise an organic acid or alkaline buffer.
  • the multiparticulate beads can comprise a solid solution of the drug compound and crystallization inhibitor.
  • the drug delivery system can comprise a matrix tablet containing water-soluble particles and the drug compound.
  • the matrix tablet can further comprise hydrophilic and hydrophobic polymers.
  • particles in the micron size range are used.
  • nanoparticle colloidal carriers composed of natural or synthetic polymers are used.
  • a controlled release formulation is a delayed release form.
  • a delayed release form can be formulated to delay a compound's action for an extended period of time.
  • a delayed release form can be formulated to delay the release of an effective dose of one or more compounds, for example, for about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, or about 24 hours.
  • a controlled release formulation can be a sustained release form.
  • a sustained release form can be formulated to sustain, for example, the compound's action over an extended period of time.
  • a sustained release form can be formulated to provide an effective dose of any compound described herein (e.g., provide a physiologically-effective blood profile) over about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, or about 24 hours.
  • a tablet providing a sustained or controlled release can comprise a first layer containing one or two of the compounds described herein, and a tablet core containing one or two other compounds.
  • the core can have a delayed or sustained dissolution rate.
  • Other exemplary embodiments can include a barrier between the first layer and core, to limit drug release from the surface of the core. Barriers can prevent dissolution of the core when the pharmaceutical formulation is first exposed to gastric fluid.
  • a barrier can comprise a disintegrant, a dissolution-retarding coating (e.g., a polymeric material, for example, an enteric polymer such as a Eudragit polymer), or a hydrophobic coating or film, and can be selectively soluble in either the stomach or intestinal fluids. Such barriers permit the compounds to leach out slowly.
  • the barriers can cover substantially the whole surface of the core.
  • Non-limiting examples of pharmaceutically-acceptable excipients can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington 's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkinsl999), each of which is incorporated by reference in its entirety.
  • compositions described herein can be in unit dosage forms suitable for single administration of precise dosages.
  • the formulation is divided into unit doses containing appropriate quantities of one or more compounds.
  • the unit dosage can be in the form of a package containing discrete quantities of the formulation.
  • Non- limiting examples are packaged tablets or capsules, and powders in vials or ampoules.
  • Aqueous suspension compositions can be packaged in single-dose non-reclosable containers. Multiple- dose reclosable containers can be used, for example, in combination with a preservative.
  • Formulations for parenteral injection can be presented in unit dosage form, for example, in ampoules, or in multi-dose containers with a preservative.
  • a compound described herein can be present in a composition in a range of from about 1 mg to about 2000 mg; from about 100 mg to about 2000 mg; from about 10 mg to about 2000 mg; from about 5 mg to about 1000 mg, from about 10 mg to about 500 mg, from about 50 mg to about 250 mg, from about 100 mg to about 200 mg, from about 1 mg to about 50 mg, from about 50 mg to about 100 mg, from about 100 mg to about 150 mg, from about 150 mg to about 200 mg, from about 200 mg to about 250 mg, from about 250 mg to about 300 mg, from about 300 mg to about 350 mg, from about 350 mg to about 400 mg, from about 400 mg to about 450 mg, from about 450 mg to about 500 mg, from about 500 mg to about 550 mg, from about 550 mg to about 600 mg, from about 600 mg to about 650 mg, from about 650 mg to about 700 mg, from about 700 mg to about 750 mg, from about 750 mg to about 800 mg, from about 800 mg to about 850 mg, from about 850 mg to about 900
  • a compound described herein can be present in a composition in an amount of about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, or about 2000 mg.
  • a dose can be expressed in terms of an amount of the drug divided by the mass of the subject, for example, miligrams of drug per kilograms of subject body mass.
  • CW178 is present in a composition in an amount ranging from about 250 mg/kg to about 2000 mg/kg, about 10 mg/kg to about 800 mg/kg, about 50 mg/kg to about 400 mg/kg, about 100 mg/kg to about 300 mg/kg, or about 150 mg/kg to about 200 mg/kg.
  • CW229 is present in a composition in an amount ranging from about 10 mg/kg to about 300 mg/kg, about 2 mg/kg to about 200 mg/kg, about 3 mg/kg to about 100 mg/kg, about 5 mg/kg to about 75 mg/kg, about 10 mg/kg to about 50 mg/kg or about 20 mg/kg to about 40 mg/kg.
  • a composition comprises from about 100 mg to about 2000 mg of CW178, from about 3 mg to about 100 mg of CW229.
  • a compound described herein is present in a composition in an amount that is a fraction or percentage of the maximum tolerated amount.
  • the maximum tolerated amount can be as determined in a subject, such as a mouse or human.
  • the fraction can be expressed as a ratio of the amount present in the composition divided by the maximum tolerated dose.
  • the ratio can be from about 1/20 to about 1/1.
  • the ratio can be about 1/20, about 1/19, about 1/18, about 1/17, about 1/16, about 1/15, about 1/14, about 1/13, about 1/12, about 1/11, about 1/10, about 1/9, about 1/8, about 1/7, about 1/6, about 1/5, about 1/4, about 1/3, about 1/2, or about 1/1.
  • the ratio can be 1/20, 1/19, 1/18, 1/17, 1/16, 1/15, 1/14, 1/13, 1/12, 1/11, 1/10, 1/9, 1/8, 1/7, 1/6, 1/5, 1/4, 1/3, 1/2, or 1/1.
  • the ratio can be about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%.
  • the ratio can be in a range from about 5% to about 100%, from about 10% to about 100%), from about 5%> to about 80%>, from about 10%> to about 80%>, from about 5%> to about 60%), from about 10%> to about 60%>, from about 5%> to about 50%>, from about 10%> to about 50%), from about 5%> to about 40%>, from about 10%> to about 40%>, from about 5%> to about 20%, or from about 10% to about 20%.
  • the maximum tolerated dose of Metformin is 2000 mg in man.
  • the maximum tolerated dose of SB681323 is 25 mg in man.
  • Dosages can be altered depending on a number of variables, including, for example, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.
  • a dose can be modulated to achieve a desired pharmacokinetic or
  • pharmacodynamics profile such as a desired or effective blood profile, as described herein.
  • Pharmacokinetic and Pharmacodynamic Measurements are described herein.
  • Pharmacokinetic and pharmacodynamic data can be obtained by techniques known in the art. Appropriate pharmacokinetic and pharmacodynamic profile components describing a particular composition can vary due to the inherent variation in pharmacokinetic and pharmacodynamic parameters of drug metabolism in human subjects. Pharmacokinetic and pharmacodynamic profiles can be based on the determination of the mean parameters of a group of subjects. The group of subjects includes any reasonable number of subjects suitable for determining a representative mean, for example, 5 subjects, 10 subjects, 16 subjects, 20 subjects, 25 subjects, 30 subjects, 35 subjects, or more. The mean is determined by calculating the average of all subject's measurements for each parameter measured.
  • the pharmacokinetic parameters can be any parameters suitable for describing a compound disclosed herein.
  • the C max can be not less than about 100 ng/mL; not less than about 200 ng/mL; not less than about 300 ng/mL; not less than about 400 ng/mL; not less than about 500 ng/mL; not less than about 600 ng/mL; not less than about 700 ng/mL; not less than about 800 ng/mL; not less than about 900 ng/mL; not less than about 1000 ng/mL; not less than about 1250 ng/mL; not less than about 1500 ng/mL; not less than about 1750 ng/mL; not less than about 2000 ng/mL; or any other C max appropriate for describing a pharmacokinetic profile of a compound described herein.
  • the T max of a compound described herein can be, for example, not greater than about 0.5 hours, not greater than about 1.0 hours, not greater than about 1.5 hours, not greater than about 2.0 hours, not greater than about 2.5 hours, not greater than about 3.0 hours, or any other T max appropriate for describing a pharmacokinetic profile of a compound described herein.
  • the AU o-inf) of a compound described herein can be, for example, not less than about 250 ng » hr/mL, not less than about 500 ng » hr/mL, not less than about 1000 ng » hr/mL, not less than about 1500 ng » hr/mL, not less than about 2000 ng » hr/mL, not less than about 3000 ng » hr/mL, not less than about 3500 ng » hr/mL, not less than about 4000 ng » hr/mL, not less than about 5000 ng » hr/mL, not less than about 6000 ng » hr/mL, not less than about 7000 ng » hr/mL, not less than about 8000 ng » hr/mL, not less than about 9000 ng » hr/mL, or any other AU o-inf) appropriate for describing a pharmacokinetic profile of a compound
  • the plasma concentration of a compound described herein about one hour after administration can be, for example, not less than about 25 ng/mL, not less than about 50 ng/mL, not less than about 75 ng/mL, not less than about 100 ng/mL, not less than about 150 ng/mL, not less than about 200 ng/mL, not less than about 300 ng/mL, not less than about 400 ng/mL, not less than about 500 ng/mL, not less than about 600 ng/mL, not less than about 700 ng/mL, not less than about 800 ng/mL, not less than about 900 ng/mL, not less than about 1000 ng/mL, not less than about 1200 ng/mL, or any other plasma concentration of a compound described herein.
  • the pharmacodynamic parameters can be any parameters suitable for describing compositions of the disclosure.
  • the pharmacodynamic profile can exhibit decreases in viability phenotype for the tumor cells or tumor size reduction in tumor cell lines or xenograft studies, for example, about 24 hours, about 48 hours, about 72 hours, or 1 week.
  • the T max is 1.2 hours; the Tl/2 is 13 hours (with a peak at 17.5 hours for an active metabolite), and AUC 0-24 hr 26,811 +- 7055 ng.hr/ml with 2000mg q.d. after dinner .
  • the C max is 0.925 ⁇ g/mL (with a peak at 0.115 for an active metabolite).
  • the T max is 0.75 hours, the Tl/2 is 10 hours, C max is 33 ng/ml with a dosing of 7.5 mg/day.
  • AUC 0-24 firs at the same dosing of 7.5 mg/day is 125 ng.hr/ml.
  • Type Small Molecule inhibitor or AMPK activator.
  • Metformin improves glycemic control by improving insulin sensitivity and decreasing intestinal absorption of glucose. Metformin acts by increasing the sensitivity of liver, muscle, fat, and other tissues to the uptake and effects of insulin. These actions lower the level of sugar in the blood.
  • glucose-lowering drugs of the sulfonylurea class for example glyburide
  • metformin does not increase the concentration of insulin in the blood and, therefore, does not cause excessively low blood glucose levels
  • metformin reduced the complications of diabetes such as heart disease, blindness and kidney disease. Metformin was approved by the FDA in December 1994.
  • Glucophage TM Glucophage TM; Glucophage XR TM; Glycon TM; Novo -Metformin TM; Nu-Metformin TM; Riomet TM.
  • IUPAC name l-carbamimidamido-N,N-dimethylmethanimidamide.
  • Indication For use as an adjunct to diet and exercise to improve glycemic control in adult patients (18 years and older) with type 2 diabetes.
  • Metformin's pharmacologic mechanisms of action are different from other classes of oral antihyperglycemic agents. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. These effects are mediated by the initial activation by Metformin of AMP-activated protein kinase (AMPK), a liver enzyme that plays an important role in insulin signaling, whole body energy balance, and the metabolism of glucose and fats. Activation of AMPK is required for metformin's inhibitory effect on the production of glucose by liver cells. AMPK causes GLUT4 deployment to the plasma membrane, resulting in insulin-independent glucose uptake.
  • AMPK AMP-activated protein kinase
  • Metabolism Metformin is not metabolized.
  • an activator of AMPK can be the compound Metformin.
  • Metformin or a salt thereof is crystalline.
  • Metformin hydrochloride, a derivative salt of Metformin can be freely soluble in water, slightly soluble in alcohols, and insoluble in acetone, ether, chloroform, and methylene chloride.
  • Metformin or a salt thereof can be well-absorbed with mean absolute
  • Metformin is negligibly bound to plasma proteins.
  • Metformin therapy includes, for example, acidosis, nausea and vomiting.
  • Type Small Molecule inhibitor.
  • SB-681323 is Potent and selective p38 MAPK inhibitor. SB-681323 is known to inhibit P38 alpha and beta.
  • SB-681323 is relevant in treatment of Coronary Heart Disease
  • SB-681323 is a potent p38 MAPK alpha inhibitor.
  • p38 mitogen-activated protein kinase (MAPK) is involved in the regulation and synthesis of inflammatory mediators Hence SB-681323 is used as potential p38 MAPK inhibitor that potentially suppresses inflammation in COPD.
  • Half life Terminal Half Life is 10 hours.
  • an inhibitor of P38-MAPK can be the compound
  • compositions formulated with SB681323 can be called, for example, DCL000517, GW681323, D09602, UNII-Q3238VQW0N, or Dilmapimod.
  • DCL000517 DCL000517
  • GW681323 D09602
  • UNII-Q3238VQW0N UNII-Q3238VQW0N
  • Dilmapimod Dilmapimod.
  • SB681323 or a salt thereof is crystalline.
  • SB681323 or a salt thereof can be well-absorbed with mean absolute
  • SB681323 therapy includes, for example, cardiac and vascular disorders, headache, hemoglobin decrease, and Lower Respiratory tract infection.
  • the disclosure provides a process for preparing a composition, the composition comprising one or more compounds, wherein the compounds are CW178 and CW229, wherein the composition optionally further comprises a pharmaceutically- acceptable excipient, wherein the process comprises the step of combining the compounds and the optional excipient in any order thereof.
  • the invention provides a method for treating a subject having or suspected of having a condition and/or a mutation, wherein the condition is, for example, a solid tumor such as lung cancer, colorectal cancer, glioblastoma, or any combination thereof.
  • a solid tumor such as lung cancer, colorectal cancer, glioblastoma, or any combination thereof.
  • the invention provides a method for treating a subject having or suspected of having: a mutation(s) in the BRAF, EGFR, KRAS, beta-catenin,
  • CDKN2A, P13KCA, APC, or SMAD4 genes or family members, or any combination thereof the method comprising administering to the subject a combination of: a) a therapeutically- effective amount of an AMPK activator; and b) a therapeutically-effective amount of an inhibitor of P38-MAPK activity, wherein the administration uses one or a plurality of dosage forms, each dosage form comprising one or more inhibitors, and wherein each dosage form optionally further comprises a pharmaceutically-acceptable excipient.
  • the invention provides a use of a combination of compounds in the preparation of a medicament for the treatment of cancer and associated conditions, the compounds comprising: an activator of AMPK and an inhibitor of P38-MAPK activity.
  • the invention provides a composition for use in treating a cancer in a subject, the composition comprising: a) i) an AMPK activator; and ii) an inhibitor of P38-MAPK activity; and b) a pharmaceutically-acceptable excipient, wherein the composition is a unit dosage form.
  • the invention provides a use of a composition in formulating a medicament for treating a cancer in a subject, the composition comprising: a) i) an AMPK activator; and ii) an inhibitor of P38-MAPK activity; and b) a pharmaceutically- acceptable excipient, wherein the composition is a unit dosage form.
  • the invention provides a use of a combination of compounds in the preparation of a kit for the treatment of cancer and associated conditions, the compounds comprising: an activator of AMPK and an inhibitor of P38-MAPK activity.
  • the invention provides a kit for use in treating a cancer in a subject, the composition comprising: a) i) an AMPK activator; and ii) an inhibitor of P38-MAPK activity; and b) a pharmaceutically-acceptable excipient, wherein the composition is a unit dosage form.
  • the invention provides a use of a composition in formulating a medicament for treating a cancer in a subject, the composition comprising: a) i) an AMPK activator; and ii) an inhibitor of P38-MAPK activity; and b) a pharmaceutically- acceptable excipient, wherein the composition is a unit dosage form.
  • compositions containing compounds described herein can be administered for prophylactic and/or therapeutic treatments.
  • the compositions are administered to a subject already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition, or to cure, heal, improve, or ameliorate the condition itself.
  • Amounts effective for this use can vary based on the severity and course of the disease or condition, previous therapy, the subject's health status, weight, and response to the drugs, and the judgment of the treating physician. Pharmaceutically-acceptable amounts can be determined by routine experimentation, for example, by a dose escalation clinical trial.
  • Multiple therapeutic agents can be administered in any order or simultaneously. If simultaneously, the multiple therapeutic agents can be provided in a single, unified form, or in multiple forms, for example, as multiple separate pills. The compounds can be packed together or separately, in a single package or in a plurality of packages. One or all of the therapeutic agents can be given in multiple doses. If not simultaneous, the timing between the multiple doses may vary to as much as about a month.
  • compounds of the disclosure are administered sequentially at a time interval.
  • the time interval can range from about 1 second to about 600 minutes.
  • kits can be packaged as a kit.
  • a kit includes written instructions on the use of the compounds and compositions.
  • the instructions can provide information on the identity of the therapeutic agent(s), modes of administration, or the indications for which the therapeutic agent(s) can be used.
  • therapeutics are combined with genetic or genomic testing to determine whether that individual is a carrier of a mutant gene that is known to be correlated with certain diseases or conditions.
  • a personalized medicine approach can be used to provide companion diagnostic tests to discover a subject's predisposition to certain conditions and susceptibility to therapy. For example, a subject who is an anti-EGFR non-responder could be identified via companion diagnostics.
  • the companion diagnostic test can be performed on the patient's tumor sample.
  • Instructions on the use of a companion diagnostic test can be provided on written material packaged with a compound, composition, or kit of the disclosure.
  • the written material can be, for example, a label.
  • the written material can suggest conditions or genetic features relevant to cancer or amenable to intervention by the compounds of the disclosure.
  • the instructions provide the subject and the supervising physician with the best guidance for achieving the optimal clinical outcome from the administration of the therapy.
  • Compounds described herein can be administered before, during, or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound can vary.
  • the compounds can be used as a prophylactic and can be administered continuously to subjects with a propensity to conditions or diseases in order to prevent the occurrence of the disease or condition.
  • the compounds and compositions can be administered to a subject during or as soon as possible after the onset of the symptoms.
  • the administration of the compounds can be initiated within the first 48 hours of the onset of the symptoms, within the first 24 hours of the onset of the symptoms, within the first 6 hours of the onset of the symptoms, or within 3 hours of the onset of the symptoms.
  • the initial administration can be via any route practical, such as by any route described herein using any formulation described herein.
  • a compound can be administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease, such as, for example, from about 1 month to about 3 months.
  • the length of treatment can vary for each subject, and the length can be determined using the known criteria.
  • the invention provides a treatment for solid tumors such as lung cancer, colorectal cancer, pancreatic cancer, glioblastoma, or any condition, or combination of conditions, where the cancer harbors mutations or variants of the KRAS and BRAF genes. Mutations in KRAS and BRAF have been found in a large number of colon and lung
  • KRAS also known as Kirsten rat sarcoma viral oncogene homolog
  • KRAS protein is a GTPase that plays an important role in cell growth, and in the progression of cancer.
  • the KRAS gene can be altered (mutated), or it can be present in a wild type form within cancer cells. Presence of mutated KRAS can be an indicator of a more aggressive tumor. If the KRAS gene is mutated, then currently-available anti-EGFR therapies, such as Erbitux and Erlotinib (Tarceva), are not effective and should not be used in the treatment of those cancers.
  • the invention provides a drug and a treatment for colon and lung tumors with known mutations in the KRAS gene.
  • colorectal cancer patients harboring wild-type copies of the KRAS gene have a better response to available anti-EGFR therapies, such as Erbitux, approximately 50% of the colorectal cancer KRAS wild-type population do not respond to anti-EGFR therapies owing to the presence of BRAF or other mutations.
  • KRAS is located downstream of EGFR, and upstream of the MAPK signaling pathway, which drives cellular proliferation, and survival endpoints. Therefore, the commonly-found KRAS mutations in colon and lung cancer bypass the effects of EGFR drugs treatments targeting the EGFR receptors, and can require further treatment such as the treatment provided by the invention.
  • the invention provides a drug and a treatment for colon and lung tumors with known mutations in the BRAF gene.
  • the BRAF gene makes a protein called B-RAF, which is involved in cell growth signaling.
  • a mutated version of the gene can increase the growth and spread of colorectal cancer cells. This mutation in the BRAF gene has been shown to make colorectal cancers resistant to anti-EGFR therapies such as Erbitux.
  • compositions of the disclosure were analyzed on a virtual tumor cell system designed to represent the disease state, and customized to match a specific molecular profile of specific cancer baselines. These experiments have also been validated with in-vitro data as depicted in Examples 1 to 8.
  • H1299 human lung cancer cell line harboring the following mutations: KRAS over- activation, PTEN deletion, CDKN2A deletion, and P53 deletion;
  • HCT116 human colon cancer cell line harboring the following mutations: KRAS over- activation, PIK3CA over-expression, B-catenin over-expression; CDKN2A deletion, COX2 deletion, and BCL2 over-expression; and
  • MDA-MB-231 human breast cancer cell line harboring the following mutations: KRAS over-activation, BRAF over-expression, CDKN2A deletion, Integrin over-expression, annexin 1 over-expression, and P53 mutation.
  • the system was first simulated with the respective oncogenic mutations aligned to the specific profiles, and then cultured for a minimum of about 35 hours of simulation time.
  • the culture time was selected to allow the system to attain the severe oncogenic state through activation of autocrine and paracrine pathway loops affecting all oncogenic mediators like growth factors, kinases, and transcription factors.
  • a system customized to the above tumor profiles was created.
  • CW178 is Metformin (AMPK activator); CW229 is SB202190 (P38 MAPK inhibitor); and CWG89 is a combination of Metformin and SB202190.
  • the Figures reflect the simulated dosing for the virtual experiments.
  • Virtual Tumor cell and the cells were cultured for a minimum of about 18-20 hours of simulation time.
  • the drug administration was performed at multiple dosage ratios across an array of samples for each drug.
  • the effect of the multiple dosage ratios was evaluated after about 18-20 hours of culture by assaying the extent of decrease/increase in the tumor cell survival, apoptosis, and proliferation markers.
  • the major markers assayed include CCND1 and CDK-Cyclin complexes responsible for cell proliferation.
  • Other proteins including BCL2, BIRC5, BAX, CASP3, and PARPl cleaved were assayed to determine their effect on tumor cell survival and apoptosis.
  • Other vital biomarkers including VEGFA were assayed to estimate the levels of angiogenesis.
  • an overall viability score was calculated as a ratio of survival/apoptosis.
  • Viability is a scale to measure change in tumorogenic symptoms. A reduction greater than 30% in tumorogenic symptoms is considered moderately effective and a reduction greater than 50% is considered an effective therapy.
  • Figure 1 illustrates the scientific rationale underlying the present disclosure, along with illustration of the biochemical targets implicated in the relevant oncogenic pathways.
  • Figure 1 illustrates the activation of the AMP-activated protein kinase (AMPK) cell signaling pathway by CW178, and inhibition of cell signaling downstream of P38 mitogen-activated protein kinases by CW229.
  • AMPK AMP-activated protein kinase
  • Figure 2 and 3 illustrate the computer-simulated dose response curves for the HCTl 16, MDA-MB-231, and HI 299 cell lines treated with individual drugs CW178 and CW229 respectively.
  • Figures 4a, 4b, and 4c illustrate the simulated efficacies of individual drugs, and combinations thereof, in terms of viability on the selected tumor profiles.
  • the individual bars represent the efficacy of CW178, CW229, and CWG89.
  • the CWG89 bar the IC30 concentration of each drug was used. The percent change seen in viability in the profiles is been tabulated below.
  • Figures 5a, b, c, and d illustrate the effect of CWG89 on key bio-markers in the selected tumor profiles.
  • the data corresponding to these figures is tabulated below.
  • Figure 6 compares the efficacy of combinations of the disclosure with known/existing drug-Erlotinib, which is approved, and currently a market leader in lung cancer therapy. The comparison was done across clinically-measurable parameters of viability. The decrease in viability seen in HI 299, HCTl 16, and MDA-MB-231 with erlotinib is much less than 10%. In comparison to this response, the decrease seen in all three tumor profiles is 30% or greater with CWG89. The data corresponding for this figure is tabulated below.
  • EXAMPLE 1 Effect of CW178 on H1299 human nine cancer cell line-PHASE 1 Study.
  • NCI-H1299 was procured from ATCC (American Type Culture Collection,
  • NCI-H1299 (CRL-5803TM) was cultured in BD Falcon (353109) tissue culture flask with vented cap T25 in RPMI 1640 (Invitrogen 22400-071) supplemented with 10% fetal bovine serum (Invitrogen 10437-010), IX MEM Sodium Pyruvate Solution (Invitrogen 11360- 070) and IX penicillin and streptomycin (Invitrogen 15140-122) in a humidified, 5% C0 2 , 37 °C incubator.
  • RPMI 1640 Invitrogen 22400-071
  • IX MEM Sodium Pyruvate Solution Invitrogen 11360- 070
  • IX penicillin and streptomycin Invitrogen 15140-122
  • a dose response for CW178 was studied on HI 299 to determine the appropriate dose of compounds to test in Phase II. The compounds were tested in duplicate. The treatments were evaluated in triplicate.
  • CW178 was procured from Sigma-Aldrich Co. LLC, St. Louis, MO; Catalog #
  • compound was delivered in 50ul volume into each well of a 96- well tissue culture plate (Corning® Costar® 3596) in triplicate.
  • EXAMPLE 2 Effect of CW178 on HCT116 human colon cancer cell line - Phase 1 Study. Experimental Protocol
  • HCT116 was procured from ATCC (American Type Culture Collection,
  • HCT 116 (CCL-247TM) were cultured in BD Falcon (353109) tissue culture flask with vented cap T25 in McCoy's 5 A Modified (Invitrogen 16600-082) supplemented with 10% fetal bovine serum and penicillin and streptomycin in a humidified, 5% C0 2 , 37 °C incubator.
  • a dose response for CW178 was studied on HCT116 to determine the appropriate dose of compounds to test in Phase II.
  • the compounds were tested in dublicate.
  • the treatments were evaluated in triplicate.
  • CW178 was procured from Sigma-Aldrich Co. LLC, St. Louis, MO; Catalog #
  • Compound stock solutions were prepared using aseptic techniques. The compounds remained in stock solution in soluble form with no visible precipitation observed. Due to the low solubility of CW178, a 100 mM stock solution was prepared fresh on the day of experiment using cell growth media. [00287] Once prepared, compound was delivered in 50 ul volume into each well of a 96- well tissue culture plate (Corning® Costar® 3596) in triplicate.
  • EXAMPLE 3 Effect of CW178 on MDA-MB-231 human breast cancer cell line - Phase 1
  • MDA-MB-231 was procured from ATCC (American Type Culture Collection,
  • MDA-MB-231 (HTB-26TM) was cultured in BD Falcon (353109) tissue culture flask with vented cap T25 in McCoy's 5 A Modified (Invitrogen 16600-082) supplemented with 10% fetal bovine serum and penicillin and streptomycin in a humidified, 5% C0 2 , 37 °C incubator.
  • CW178 was procured from Sigma-Aldrich Co. LLC, St. Louis, MO; Catalog #
  • compound was delivered in 50 ul volume into each well of a 96- well tissue culture plate (Corning® Costar® 3596) in triplicate.
  • EXAMPLE 4 Effect of CW229 on H1299 human lung cancer cell line - Phase 1 Study,
  • the NCI-H1299 was procured from ATCC (American Type Culture Collection,
  • NCI-H1299 (CRL-5803TM) was cultured in BD Falcon (353109) tissue culture flask with vented cap T25 in RPMI 1640 (Invitrogen 22400-071) supplemented with 10% fetal bovine serum (Invitrogen 10437-010), IX MEM Sodium Pyruvate Solution (Invitrogen 11360- 070) and IX penicillin and streptomycin (Invitrogen 15140-122) in a humidified, 5% C0 2 , 37 °C incubator.
  • RPMI 1640 Invitrogen 22400-071
  • IX MEM Sodium Pyruvate Solution Invitrogen 11360- 070
  • IX penicillin and streptomycin Invitrogen 15140-122
  • a dose response for CW229 was studied on HI 299 to determine the appropriate dose of compounds to test in Phase II. The compounds were tested in duplicate. The treatments were evaluated in triplicate.
  • C W229 was procured from Selleck Chemicals, Houston, TX; Catalog # S 1077.
  • compound was delivered in 50 ul volume into each well of a 96- well tissue culture plate (Corning® Costar® 3596) in triplicate.
  • CW229 showed a progressively higher reduction in cell viability with increasing dosages and caused a decrease of -80% at 75 uM (Figure 10).
  • the data corresponding to the figure is tabulated below.
  • EXAMPLE 5 Effect of CW229 on HCT116 human colon cancer cell line - Phase 1 Study. Experimental Protocol
  • HCT116 was procured from ATCC (American Type Culture Collection,
  • HCT116 CCL-247TM were cultured in BD Falcon (353109) tissue culture flask with vented cap T25 in McCoy's 5 A Modified (Invitrogen 16600-082) supplemented with 10%> fetal bovine serum and penicillin and streptomycin in a humidified, 5% C0 2 , 37 °C incubator.
  • a dose response for CW229 was studied on HCT116 to determine the appropriate dose of compounds to test in Phase II. The compounds were tested in duplicate. The treatments were evaluated in triplicate.
  • CW229 was procured from Selleck Chemicals, Houston, TX; Catalog # S1077.
  • compound was delivered in 50 ul volume into each well of a 96- well tissue culture plate (Corning® Costar® 3596) in triplicate.
  • EXAMPLE 6 Effect of CW229 on MDA-MB-231 human breast cancer cell line - Phase 1
  • MDA-MB-231 was procured from ATCC (American Type Culture Collection,
  • MDA-MB-231 (HTB-26TM) was cultured in BD Falcon (353109) tissue culture flask with vented cap T25 in McCoy's 5 A Modified (Invitrogen 16600-082) supplemented with 10% fetal bovine serum and penicillin and streptomycin in a humidified, 5% C0 2 , 37 °C incubator.
  • a dose response for CW229 was studied on MDA-MB-231 to determine the appropriate dose of compounds to test in Phase II. The compounds were tested in duplicate. The treatments were evaluated in triplicate.
  • C W229 was procured from Selleck Chemicals, Houston, TX; Catalog # S 1077.
  • NCI-H1299 was procured from ATCC and cultured as explained in examples
  • Phase II evaluated the effects of combination of C Wl 78 and C W229 on cell viability against HI 299.
  • Group2 Low dosage: A two drug combination was administered with a dosage composition of CW229 (SB202190) - 30 uM CW178 (Metformin)- 30 mM
  • Group3 High dosage: A two drug combination was administered with a dosage composition of CW229 (SB202190) - 45 uM
  • EXAMPLE 8 Effect of CWG89 on HCT116 human colon cancer cell line- Phase II Study. Experimental Protocol
  • the HCT116 was procured from ATCC and cultured as explained in examples 2 and 5 above.
  • Phase II evaluated the effects of combination of C Wl 78 and C W229 on cell viability against HCT116.
  • Group2 Low dosage: A two drug combination was administered with a dosage composition of CW229 (SB202190) - 30 uM
  • Group3 High dosage: A two drug combination was administered with a dosage composition of CW229 (SB202190) - 45 uM
  • the MDA-MB-231 was procured from ATCC and cultured as explained in examples 3 and 6 above.
  • Phase II evaluated the effects of combination of C Wl 78 and C W229 on cell viability against MDA-MB-231.
  • Group2 Low dosage: A two drug combination was administered with a dosage composition of CW229 (SB202190) - 30 uM
  • Group3 High Dosage: A two drug combination was administered with a dosage composition of CW229 (SB202190) - 45 uM
  • Group4 A two drug combination was administered with a dosage composition of
  • Group4 A two drug combination was administered with a dosage composition of
  • Synergistic inhibitory effect is defined by a magnitude of inhibition of cell viability by two or three compounds that is greater than the sum of the magnitude of inhibition of each constituent compound.
  • a synergistic effect of the combination CWG89 is seen, as illustrated in the table below, comparing the effect of individual drugs CW178 and CW229 with the combination CWG89 in the NCI-H1299 cell line. (Data corresponding to figures 17 and 19).
  • EXAMPLE 12 Comparative analysis between CW178 and CWG89 on the HCT116 human colon cancer cell line
  • Group4 A two drug combination was administered with a dosage composition of
  • EXAMPLE 13 Comparative analysis between CW229 and CWG89 on the HCT116 human colon cancer cell line
  • Group4 A two drug combination was administered with a dosage composition of
  • Synergistic inhibitory effect is defined by a magnitude of inhibition of cell viability by two or three compounds that is greater than the sum of the magnitude of inhibition of each constituent compound.
  • a synergistic effect of the combination CWG89 is seen, as illustrated in the table below, comparing the effect of individual drugs CW178 and CW229 with the combination CWG89 in the HCTl 16 cell line. (Data corresponding to figures 21 and 23).
  • EXAMPLE 14 Comparative analysis between CW178 and CWG89 on the MDA-MB-231 human colon cancer cell line
  • Group4 A two drug combination was administered with a dosage composition of
  • EXAMPLE 15 Comparative analysis between CW229 and CWG89 on the MDA-MB-231 human colon cancer cell line
  • Group4 A two drug combination was administered with a dosage composition of
  • Synergistic inhibitory effect is defined by a magnitude of inhibition of cell viability by two or three compounds that is greater than the sum of the magnitude of inhibition of each constituent compound.
  • a synergistic effect of the combination CWG89 is seen, as illustrated in the table below, comparing the effect of individual drugs CW178 and CW229 with the combination CWG89 in the MDA-MB-231 cell line. (Data corresponding to figures 25 and 27).

Abstract

The present disclosure describes a composition and a kit having a combination of compounds for use in the treatment of cancer and associated conditions and therapies. The disclosure also relates to a process of obtaining the composition and the method of treating cancer and associated conditions by administration of the compositions.

Description

COMPOSITIONS, PROCESS OF PREPARATION OF SAID COMPOSITIONS AND
METHOD OF TREATING CANCER
CROSS REFERENCE
[0001] This application claims priority to Indian Provisional Patent Application No.
4232/CHE/2011, filed on December 5, 2011, which is incorporated by reference herein in its entirety.
INCORPORATION BY REFERENCE
[0002] Every patent, patent application, and non-patent publication recited herein is incorporated by reference in its entirety as if each patent, patent application, and non-patent publication had been incorporated by reference individually.
TECHNICAL FIELD
[0003] Embodiments of the disclosure describe compositions and kits, each containing compounds for use in the treatment of cancer, and associated therapies. The disclosure also provides processes for obtaining the compositions and methods of treatment by administration of the compositions.
BACKGROUND OF THE DISCLOSURE
[0004] Cancer is a group of more than 100 diseases characterized by uncontrolled cell proliferation, and the acquisition of the ability to migrate, and invade, tissues and organs within different sites of the body by transformed cells. Although cancer can arise in virtually any of the body's tissues, each type of cancer has unique features. The basic processes that produce cancer are quite similar in all forms of the disease.
[0005] Cancer can be broadly classified into different categories. Carcinomas are characterized by tumors, or cell masses, that reside within internal and external parts of the body such as the lung, breast, and colon. Sarcomas are characterized by tumors that reside within bone, cartilage, fat, connective tissue, muscle, and other supportive tissues. Lymphomas are cancers that begin in the lymph nodes and immune system tissues. Leukemias are cancers that begin in the bone marrow and often mobilize into the bloodstream. Adenomas are cancers that arise in the thyroid, the pituitary gland, the adrenal gland, and other glandular tissues.
[0006] Most cancers are characterized by de-regulation of multiple signaling pathways, and loss of cross-talk between them. When a cell breaks free from the normal restraints on cell division, and begins to follow its own agenda for proliferation, a mass of cells, or a tumor, produced by the division of this first, ancestral cell, will arise. The progeny of the founder cell(s) will display the same inappropriate proliferation pattern(s), and the abnormal cell population will either remain within the tissue in which it originated, or they will begin to invade nearby tissues. The invasion of nearby tissues is known as metastasis.
[0007] Tumors threaten an individual's life when their growth disrupts the function of tissues, and/or organs, needed for survival. An invasive, or metastatic, tumor is said to be malignant. Metastatic cells can establish new tumors (metastases) elsewhere in the body. When mutations within a cancerous cell render the cell unable to stop uncontrolled division, growth, and tissue invasion, malignant tumors thrive. Mutations that inhibit tumor suppressor genes, suicide, and activate oncogene function, thereby not allowing cell(s) to regulate the cell machinery, result in unchecked division of cells, and the formation of tumors.
SUMMARY OF THE INVENTION
[0008] In some embodiments, the invention provides a composition comprising: a) i) an AMPK activator; and ii) an inhibitor of P38-MAPK activity; and b) a pharmaceutically-acceptable excipient, wherein the composition is a unit dosage form.
[0009] In some embodiments, the invention provides a kit comprising: a) i) an AMPK activator; and ii) an inhibitor of P38-MAPK activity; and b) written instructions on use of the kit.
[0010] In some embodiments, the invention provides a method for treating a cancer in a subject in need or want of relief thereof, the method comprising administering to the subject: i) a therapeutically-effective amount of an AMPK activator; and ii) a therapeutically-effective amount of an inhibitor of P38-MAPK activity.
BRIEF DESCRIPTION OF THE FIGURES
[0011] Figure 1 illustrates schematics of scientific rationale.
[0012] Figure 2 illustrates the dose response effect for CW178 across the selected tumor profiles.
[0013] Figure 3 illustrates the dose response effect for CW229 across the selected tumor profiles.
[0014] Figure 4a illustrates the efficacy of individual drugs CW178 and CW229, and the efficacy of combination drug CWG89in terms of Viability on H1299.
[0015] Figure 4b illustrates the efficacy of individual drugs CW178 and CW229, and the efficacy of combination drug CWG89 in terms of Viability on HCT116. [0016] Figure 4c illustrates the efficacy of individual drugs CW178 and CW229, and the efficacy of combination drug CWG89in terms of Viability on MDA-MB-231.
[0017] Figure 5a illustrates the effect of individual drugs CW178 and CW229 and the combination CWG89 on phosphorylated AKT in selected tumor profiles
[0018] Figure 5b illustrates the effect of individual drugs CW178 and CW229 and the combination CWG89 on BAX dimers in selected tumor profiles
[0019] Figure 5c illustrates the effect of individual drugs CW178 and CW229 and the combination CWG89 on CDK4-CCND1 complex in selected tumor profiles
[0020] Figure 5d illustrates the effect of individual drugs CW178 and CW229 and the combination CWG89 on VEGFA levels in selected tumor profiles
[0021] Figure 6 illustrates the comparison of the efficacy of combination of the compounds on clinical parameter of viability with Erlotinib. Erlotnib (TARCEVA®), is approved and is currently a market leader.
[0022] Figure 7 illustrates the dose response effect for CW178 on viability of NCI-H1299 cells.
[0023] Figure 8 illustrates the dose response effect for CW178 on viability of HCTl 16 cells.
[0024] Figure 9 illustrates the dose response effect for CW178 on viability of MDAMB231 cells.
[0025] Figure 10 illustrates the dose response effect for CW229 on viability of H1299 cells.
[0026] Figure 11 illustrates the dose response effect for CW229 on viability of HCTl 16 cells.
[0027] Figure 12 illustrates the dose response effect for CW229 on viability of MDAMB231 cells.
[0028] Figure 13 illustrates the effect of the combination of two drugs CWG89 on H1299 cells at low and high dosage.
[0029] Figure 14 illustrates the effect of the combination of two drugs CWG89 on HCTl 16 cells at low and high dosage.
[0030] Figure 15 illustrates the effect of the combination of two drugs CWG89 on MDAMB231 cells at low and high dosage.
[0031] Figure 16 illustrates the comparison of the individual effect of CW178 with the combination of two drugs CWG89 on H1299-virtual baseline.
[0032] Figure 17 illustrates the comparison of the individual effect of CW178 with the combination of two drugs CWG89 on HI 299 cells.
[0033] Figure 18 illustrates the comparison of the individual effect of CW229 with the combination of two drugs CWG89 on H1299-virtual baseline.
[0034] Figure 19 illustrates the comparison of the individual effect of CW229 with the combination of two drugs CWG89 on HI 299 cells.
[0035] Figure 20 illustrates the comparison of the individual effect of CW178 with the combination of two drugs CWG89 on HCT116-virtual baseline.
[0036] Figure 21 illustrates the comparison of the individual effect of CW178 with the combination of two drugs CWG89 on HCT116 cells.
[0037] Figure 22 illustrates the comparison of the individual effect of CW229 with the combination of two drugs CWG89 on HCT116-virtual baseline.
[0038] Figure 23 illustrates the comparison of the individual effect of CW229 with the combination of two drugs CWG89 on HCT116 cells.
[0039] Figure 24 illustrates the comparison of the individual effect of CW178 with the combination of two drugs CWG89 on MDAMB231 -virtual baseline.
[0040] Figure 25 illustrates the comparison of the individual effect of CW178 with the combination of two drugs CWG89 on MDAMB231 cells.
[0041] Figure 26 illustrates the comparison of the individual effect of CW229 with the combination of two drugs CWG89 on MDAMB231 -virtual baseline.
[0042] Figure 27 illustrates the comparison of the individual effect of CW229 with the combination of two drugs CWG89 on MDAMB231 cells.
DETAILED DESCRIPTION OF INVENTION
[0043] Treatment of carcinomas can involve surgery, systemic therapy, therapies in
interventional radiology, chemotherapy, radiation therapy, and/or immunotherapy. Some patients can pursue one or more of these therapies in the management of their disease. These therapies can remove or destroy cancer in a particular area of the body, yet they involve expensive, and painful, procedures that are not always effective.
[0044] Some cancers, such as the carcinomas found within non-small cell lung cancer (NSCLC), and colorectal cancers, can be insensitive to conventional chemotherapy, radiation, and/or other standard-of-care treatments. In many diagnoses of early-stage carcinomas, surgery is often chosen as the treatment of choice if diagnosed at an early stage.
[0045] Available standard chemotherapy regimens targeting NSCLC include platinum-based therapies, such as cisp latin, vinca alkaloids, and/or a combination of both. Platinum based therapies, as exemplified by cisplatin, inhibit DNA repair and/or DNA synthesis in cancer cells by cross-linking DNA. Vinca alkaloids target cancerous cells by destroying cellular structures necessary for cell growth, the mitotic spindles. The combination of chemotherapies with different mechanisms of action, such as platinum and Paclitaxel, which inhibits cell division by binding to mitotic spindles rather than destroying them like vinca alkaloids do, modestly improves tumor response, and consequently survival, in NSCLC. However, even though some NSCLC patients are initially responsive to this therapy, most patients relapse and die from the disease. With available treatments, the 5-year survival rate for NSCLC patients can be approximately 15%.
[0046] The current standard-of-treatment options, and current prognosis, are just as dreadful for patients diagnosed with colorectal carcinomas. Available therapies for colorectal cancers can include chemotherapy regimens including: a) Fluorouracil (5-FU), a drug that inhibits the enzyme thymidylate synthase, and blocks the synthesis of a nucleoside required for DNA replication; b) capecitabine (Xeloda), a drug that is converted into 5-FU within the tumor; c) folinic Acid (Leucovorin), a derivative of tetrahydro folic acid with vitamin activity that can be used as an adjuvant in combination with 5-FU to allow for some DNA synthesis during the course of chemotherapy; d) irinotecan (Camptosar), a drug that inhibits both DNA replication and gene transcription by inhibiting the enzyme topoisomerase I; e) Mitomycin C, which functions as a potent DNA crosslinker, preventing DNA replication and transcription, which can result in cell death; e) Oxaliplatin (Eloxatin), which functions by forming both inter- and intra- strand cross links in DNA; f) Raltitrexed (Tomudex), which is a chemical analogue of folic acid, and prevents the formation of new DNA and RNA; and g) Tegafur-Uracil (UFT), a drug that is converted to 5-FU within cells that uptake the drug. The prognosis for patients diagnosed with colon cancer varies significantly depending on the stage of cancer, but the five-year survival rate remains as low as 6% for stage IV colon cancer patients.
[0047] Additional available therapies to treat colorectal, and non-small cell lung cancer
(NSCLC) cancer patients, include a variety of EGFR inhibitors. Cetuximab is available for treatment of colorectal cancers. Erlotinib is available for treating NSCLC. Although these can be useful in treating aspects of the disease, the drugs must be administered in a pre-specified sequence or in combination with other drugs.
[0048] Furthermore, in both colon and NSCLC cancer, the success achieved with standard-of- care doses of single agents has been limited. Obstacles to increasing the currently prescribed doses include concerns about exceeding a therapeutic window and further damaging normal physiology, and/or concerns about the manifestation of additional undesirable side effects at higher doses. Improved treatment protocols for this complex and devastating disorder are greatly needed. A safe and effective treatment that could alleviate suffering, and improve outcomes would be a significant medical advance for cancer treatment, and potentially for the treatment of other end-stage diseases as well. [0049] Most of the above chemotherapeutic drugs are associated with side effects of fatigue, diarrhea, mouth sores, nausea and vomiting, decreased white blood count with increased risk of infection, decreased platelet count with increased risk of bleeding, decreased red blood count with increased risk of tiredness, and numbness of hand and feet. In general, the overall quality of life of a patient undergoing cancer treatment with standard chemotherapy regimens is
jeopardized, and there is a great need for dissimilar chemotherapeutic drugs, particularly if the drug can minimize the side effects of chemotherapy.
[0050] Moreover, several of the currently available treatments non-discriminately target cell division, cell proliferation, or transcription as a whole instead of targeting specific pathways within cells that are known to have been damaged, or altered, within a particular type of cancer. The present invention addresses some of the toughest challenges in cancer treatment by disclosing a novel treatment, and its use in cancer therapy.
[0051] The invention described herein provides an alternative to currently available therapies for the treatment of cancer. Notably, the invention considered treatment of cancers where other available single agent therapies, or combinations of single agent therapies, have not been successful at simultaneously treating the disease, and improving one or more undesirable symptoms associated with the disease states or treatment.
[0052] Provided herein is a drug combination and a method for treating cancer. In some embodiments, the invention intervenes in the biochemical dynamics of both lung and colorectal cancer, and constitutes a therapy designed to target viability and proliferation cellular pathways within cells. In some embodiments, the invention intervenes in biochemical pathways associated with KRAS and/or BRAF mutations in tumor cells associated with KRAS and/or BRAF mutations. In some embodiments, such a tumor cell exhibits a mutation in each of KRAS and BRAF.
[0053] In some embodiments, the disclosure provides a two-drug combination, which provides multi-targeted combination therapeutic approach to suppress and cure symptoms associated with cancer and associated conditions. The drug combinations were designed using virtual co-culture computational simulations as described herein. Simulations performed with each individual drug were validated in aligned tumor cell line profiles, and provided more than 50% marker trend correlation as described herein. In some embodiments, the two-drug combination comprises a AMPK activator and a P38-MAPK inhibitor.
[0054] The two-drug combinations provide synergistic efficacy on the end-point markers, while dosing can be as low as, for example, the IC30 value of the drug. Using a lower dose of the individual drug can provide an advantage in terms of minimizing the intensity of side-effects or toxicities associated with higher doses of the individual drugs. Also, the drug combination can inhibit multiple targets with low individual drug doses, so that an amplified effect can be observed on some or all of the primary end-point markers. Additionally, the low dosage drug combination can ensure that all the primary drug targets have some level of typical,
physiological response ability, so as to minimize or eliminate the possibility of immune suppression and secondary infections.
[0055] Use of smaller doses of individual drugs also lowers the cost of manufacture and formulation, providing an improved effect at lower price to the subject. Smaller doses can also mitigate against wasteful administration of a drug to a physiological system that has been saturated or has reached a peak therapeutic response from smaller, synergistic doses.
[0056] In some embodiments, the invention disclosed herein provides a combination of two classes of drugs, which exhibit converging antagonistic effects on major oncogenic transcription factors through different mechanisms of action. Inhibition of transcription factors such as HIF1 A, NFkB and API can cause a systemic reduction in the expression and/or activity of oncogenic kinases and growth factors that are involved in tumor disease physiology, and tumor progression. In addition to targeting multiple pathways and nodes within the tumor cell, the drug combination targets multiple cell types in the micro environment including the angiogenic endothelial cell, the stromal fibroblast cell, and also impacts tumor mediated inflammation. In some embodiments, the inhibition of multiple pathways in multiple cell types provides a much needed multi-prong therapeutic effect, at low drug concentrations.
[0057] The drug combinations provided herein are effective in EGFR-resistive systems (anti- EGFR non-responders), because the two drug compounds affect diverse (EGFR-independent) strategic signaling points distributed across two distinct pathways in the relevant cell systems. This phenomenon allows even minor inhibitory effects from each strategic point to produce an enhanced inhibitory effect upon convergence of the minor effects, thereby amplifying the effect on the pool of biomarkers.
[0058] In some embodiments, the invention provides a composition comprising: a) i) an AMPK activator; and ii) an inhibitor of P38-MAPK activity; and b) a pharmaceutically-acceptable excipient, wherein the composition is a unit dosage form.
[0059] In some embodiments, the invention provides a kit comprising: a) i) an AMPK activator; and ii) an inhibitor of P38-MAPK activity; and b) written instructions on use of the kit.
[0060] The CW178 class of drugs functions by activating AMPK.
[0061] The CW229 class of drugs can inhibit the enzyme P38-MAPK activity and can induce anti-pro liferative effects. In some embodiments, CW229 is an inhibitor of P38. [0062] As used herein, the term, "CWG89," refers to a combination of any CW178 compound, and any CW229 compound in any amount, ratio, concentration, or order thereof.
[0063] Non- limiting examples of CW178 include: a) Metformin, also known as 1,1- dimethylbiguanide, N,N-dimethyldiguanide, N'-dimethylguanylguanidine, and DMGG, or a pharmaceutically-acceptable salt thereof, such as Embonate, Hydrochloride, and/or p- Chlorophenoxyacetate salts; b) Phenformin, also known as 1-phenethylbiguanide,
phenethyldiguanide, Ν'-β-phenethylformamidinyliminourea, fenformin, fenormin, β-PEBG, PEDG, or a pharmaceutically-acceptable salt thereof, such as a hydrochloride salt; c) Panduratin, also known as (2,6-dihydroxy-4-methoxyphenyl)-[(lR,2S,6R)-3-methyl-2-(3-methylbut-2-enyl)- 6-phenylcyclohex-3-en-l-yl]methanone, or a pharmaceutically-acceptable salt thereof; d) AICAPv, also known as [(2R,3S,4R,5R)-5-(5-amino-4-carbamoylimidazol-l-yl)-3,4- dihydroxyoxolan-2-yl]methyl dihydrogen phosphate, or a pharmaceutically-acceptable salt thereof; e) CID 16760291, also known as 5-[3-[4-[2-(4- fluorophenyl)ethoxy]phenyl]propyl]furan-2-carboxylic acid, or a pharmaceutically-acceptable salt thereof; f) B-lapachone, also known as 2,2-dimethyl-3,4 dihydrobenzo[h]chromene-5,6- dione, or a pharmaceutically-acceptable salt thereof; and g) A769662, also known as 6-hydroxy- 3-[4-(2-hydroxyphenyl)phenyl]-4-oxo-7H-thieno[2,3- b]pyridine-5-carbonitrile or a
pharmaceutically-acceptable salt thereof.
[0064] Non-limiting examples of CW178 include the compounds of Table 1.
Table 1 : Examples of CW178 compounds.
Figure imgf000010_0001
5-[3-[4-[2-(4-
CID 16760291 IN1531; D942 fluorophenyl)ethoxy]phenyl]pro pyl]furan-2-carboxylic acid β-Lapachone; A-lapachone; Lapachone,
2,2-dimethyl-3,4- beta-; 4707-32-8; NSC 26326;
B-lapachone dihydrobenzo [h] chromene-5 ,6- NSC26326; NSC629749; NSC 629749;
dione
BRN 0181499
A-769662; 844499-71-4; 4-Hydroxy-3- 4-hydroxy-3-[4-(2- (2'-hydroxy- 1 , 1 '-biphenyl-4-yl)-6-oxo- hydroxyphenyl)phenyl]-6-oxo-
A769662
6,7-dihydrothieno[2,3-b]pyridine-5- 7H-thieno[2,
carbonitrile; PubCheml6661 3 -b]pyridine-5 -carbonitrile
[0065] Chemical structures of the compounds of Table 1 are as follows.
Metformin:
Figure imgf000011_0001
Panduratin:
Figure imgf000011_0002
AICAR:
Figure imgf000012_0001
(OH)2
Figure imgf000012_0002
Figure imgf000012_0003
Figure imgf000013_0001
[0066] In some embodim nts, the invention provides a compound of Formula (I):
Figure imgf000013_0002
(I), wherein
each of R1, R2, R3, R4, and R5 is independently H, OH, SH, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, or alkylheterocyclyl, wherein each alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, and alkylheterocyclyl group is independently unsubstituted or substituted, or any two of R1, R2, R3, R4, and R5 form a ring together with the atoms to which they are bound, wherein the ring is unsubstituted or substituted; each of X and Y is independently O, S, C(R6)(R7), N+(R6)(R7), or N(R6); and each of R6 and R7 is independently H, OH, SH, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, or alkylheterocyclyl, wherein each alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, and alkylheterocyclyl group is
independently unsubstituted or substituted, or R6 and R7 form a ring with the atoms to which they are bound, wherein the ring is unsubstituted or substituted, or a pharmaceutically-acceptable salt thereof.
[0067] In some embodiments, R1 and R2 form a ring with the atoms to which they are bound.
[0068] In some embodiments, R1 and R3 form a ring with the atoms to which they are bound.
[0069] In some embodiments, R2 and R3 form a ring with the atoms to which they are bound. [0070] In some embodiments, R3 and R4 form a ring with the atoms to which they are bound.
[0071] In some embodiments, R3 and R5 form a ring with the atoms to which they are bound.
[0072] In some embodiments, R4 and R5 form a ring with the atoms to which they are bound.
[0073] In some embodiments, one or both of X and Y are N(R6). In some embodiments, both of X and Y are N(R6). In some embodiments, R6 is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, or alkylheterocyclyl, wherein each alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, and alkylheterocyclyl group is independently unsubstituted or substituted. In some embodiments, R6 is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, or alkylheterocyclyl. In some embodiments, R6 is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, or alkylaryl. In some
embodiments, R6 is H, alkyl, or aryl. In some embodiments, R6 is H.
[0074] In some embodiments: each of R1, R2, R3, R4, and R5 is independently H, alkyl, alkenyl, aryl, arylalkyl, or alkylaryl, wherein each alkyl, alkenyl, aryl, arylalkyl, and alkylaryl group is independently unsubstituted or substituted; each of X and Y is independently N(R6); and each R6 is independently H, alkyl, alkenyl, aryl, arylalkyl, or alkylaryl, wherein each alkyl, alkenyl, aryl, arylalkyl, and alkylaryl, group is independently unsubstituted or substituted.
[0075] In some embodiments: each of R1, R2, R3, R4, and R5 is independently H, alkyl, alkenyl, aryl, arylalkyl, or alkylaryl, wherein each alkyl, alkenyl, aryl, arylalkyl, and alkylaryl group is independently unsubstituted or substituted; each of X and Y is independently N(R6); and each R6 is independently H, alkyl, or arylalkyl, wherein each alkyl, alkenyl, aryl, arylalkyl, and alkylaryl, group is independently unsubstituted or substituted.
[0076] In some embodiments: each of R1, R2, R3, R4, and R5 is independently H, alkyl, or arylalkyl; each of X and Y is independently N(R6); and each R6 is independently H or alkyl.
[0077] In some embodiments: each of R1, R2 and R3 is H; each of R4 and R5 is alkyl; each of X and Y is N(R6); and each R6 is H.
[0078] In some embodiments: each of R1, R2 and R3 is H; each of R4 and R5 is independently methyl, ethyl, propyl, or isopropyl; each of X and Y is independently N(R6); and each R6 is H.
[0079] In some embodiments: each of R1, R2 and R3 is H; each of R4 and R5 is methyl; each of X and Y is N(R6); and each R6 is H.
[0080] In some embodiments: each of R1, R2, R3, and R4 is H; R5 is arylalkyl; each of X and Y is N(R6); and each R6 is H.
[0081] In some embodiments: each of R1, R2, R3, and R4 is H; R5 is an arylalkyl group of the formula: Ar-(CH2)n- , wherein Ar is aryl, and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each of X and Y is N(R6); and each R6 is H. [0082] In some embodiments: each of R1, R2, R3, and R4 is H; R5 is an arylalkyl group of the formula: Ar-(CH2)n- , wherein Ar is aryl, and n is 1, 2, or 3; each of X and Y is N(R6); and each
R6 is H.
[0083] In some embodiments: each of R1, R2, R3, and R4 is H; R5 is an arylalkyl group of the formula: Ar-(CH2)n- , wherein Ar is phenyl, and n is 1, 2, or 3; each of X and Y is N(R6); and each R6 is H.
[0084] In some embodiments: each of R1, R2, R3, and R4 is H; R5 is an arylalkyl group of the formula: Ar-(CH2)n- , wherein Ar is phenyl, and n is 1 ; each of X and Y is N(R6); and each R6 is H.
[0085] In some embodiments: each of R1, R2, R3, and R4 is H; R5 is an arylalkyl group of the formula: Ar-(CH2)n- , wherein Ar is phenyl, and n is 2; each of X and Y is N(R6); and each R6 is H.
[0086] In some embodiments, the compound of Formula (I) is a compound of Formula (II):
Figure imgf000015_0001
NH N H (II), wherein each of R and R is independently H, alkyl, or arylalkyl.
[0087] In some embodiments, the compound of Formula (I) is:
Figure imgf000015_0002
In some embodiments, the compound of Formula (I) is:
Figure imgf000015_0003
[0089] In some embodiments, the compound of Formula (I) is metformin.
[0090] In some embodiments, the compound of Formula (I) is phenformin. [0091] Non- limiting examples of CW229 include: a) RWJ67657, also known as 4-[4-(4- fluorophenyl)- 1 -(3-phenylpropyl)-5-pyridin-4-ylimidazol-2-yl]but-3-yn- 1 -ol or a
pharmaceutically-acceptable salt thereof; b) ARRY-797, also known as (4-difluorophenoxy)-N- [2-(dimethylamino)ethyl]-l-(2-methylpropyl) indazole-6-carboxamide, or a pharmaceutically- acceptable salt thereof; c) SB203580, also known as 4-[4-(4-fluorophenyl)-2-(4- methylsulfinylphenyl)-lH-imidazol-5-yl] pyridine, or a pharmaceutically-acceptable salt thereof; d) PH-797804, also known as 3-[3-bromo-4-[(2,4-difluorophenyl)methoxy]-6-methyl-2- oxopyridin-l-yl]-N,4-dimethylbenzamide, or a pharmaceutically-acceptable salt thereof; e)
SB220025, also known as 4-[5-(4-fluorophenyl)-3-piperidin-4-ylimidazol-4-yl]pyrimidin-2- amine, or a pharmaceutically-acceptable salt thereof; f) SB202190, also known as 4-[4-(4- fluorophenyl)-5-pyridin-4-yl- 1 ,3-dihydroimidazol-2-ylidene]cyclohexa-2,5-dien- 1 -one, or a pharmaceutically-acceptable salt thereof; g) SB239063, also known as 4-[4-(4-fluorophenyl)-5- (2-methoxypyrimidin-4-yl)imidazol-l-yl]cyclohexan-l-ol, or a pharmaceutically-acceptable salt thereof; h) SB242235, also known as 4-[5-(4-fluorophenyl)-3-piperidin-4-ylimidazol-4-yl]-2- methoxypyrimidine, or a pharmaceutically-acceptable salt thereof; i) NPC31169, or a
pharmaceutically-acceptable salt thereof; j) SCIO-469, or a pharmaceutically-acceptable salt thereof; k) FR167653, or a pharmaceutically-acceptable salt thereof; 1) MW01 -2-069 A-SRM, or a pharmaceutically-acceptable salt thereof; m) JX401, also known as l-[2-Methoxy-4- (methylthio)benzoyl]-4-(phenylmethyl)piperidine, or a pharmaceutically-acceptable salt thereof; n) VX702, also known as 6-(N-carbamoyl-2,6-difluoroanilino)-2-(2,4- difluorophenyl)pyridine- 3-carboxamide, or a pharmaceutically-acceptable salt thereof; o) SB-681323 (GSK), or a pharmaceutically-acceptable salt thereof; p) BMS-582949, also known as N-(5- (cyclopropylcarbamoyl)-2-methylphenyl)-5 -methyl- 1 -(3 -(trifluoromethyl)pyridin-2-yl)- 1 H- pyrazole-4-carboxamide, or a pharmaceutically-acceptable salt thereof; q) DB01953, also known as 3-[2-(pyridin-4-yl)ethyl]-lH-indole, or a pharmaceutically-acceptable salt thereof; r) ARRY- 614, or a pharmaceutically-acceptable salt thereof; s) CHEMBL155448 or [4-(2-aminoanilino)- 2-chlorophenyl]-phenylmethanone or a pharmaceutically-acceptable salt thereof; s)
CHEMBL512255, also known as 3-[6-(2,4-difluoroanilino)-2H-pyrazolo[3,4-b]pyridin-3-yl]-4- methoxy-N-morpholin-4-ylbenzamide, or a pharmaceutically-acceptable salt thereof; t) LY- 2228820, also known as 5-[2-tert-butyl-4-(4-fluorophenyl)-lH-imidazol-5-yl]-3-(2,2- dimethylpropyl)imidazo[4,5-b]pyridin-2-amine, or a pharmaceutically-acceptable salt thereof such as a methanesulfonic acid salt; and u) ML3403, also known as 4-[5-(4-fluorophenyl)-2- methylsulfanyl-lH-imidazol-4-yl]-N-(l-phenylethyl)pyridin-2-amine), or a pharmaceutically- acceptable salt thereof. [0092] Non-limiting examples of CW229 include the compounds of Table 2.
Table 2: Examples of CW229 compounds.
Figure imgf000017_0001
CHEMBL155448 [4-(2-aminoanilino)-2-
CHEBL354329 chlorophenyl]- phenylmethanone
CHEMBL512255 3- [6-(2,4-difluoroanilino)-2H- pyrazolo[3,
CHEBL588685
4- b]pyridin-3-yl]-4-methoxy- N-morpholin-4-ylbenzamide
C15H14N2; AC1L1E9J; 3 - [2-(pyridin-4-yl)ethyl] - 1 H-
DB01953
CHEMBL193156 indole
4-(5-(Cyclopropylcarbamoyl)-
2-methylphenylamino)-5 -
BMS-582949 methyl-N-propylpyrro lo [ 1 ,2- fj [ 1 ,2,4]triazine-6- carboxamide
8-(2,6-difhiorophenyl)-2-(l ,3- dihydroxypropan-2-ylamino)-
DCL000517; GW 681323; D09602;
SB 681323 4-(4-fluoro-2-
UNII-Q3238VQW0N; C23H19F3N403
methy lpheny l)pyrido [2,3- d]pyrimidin-7-one
5-[2-tert-butyl-4-(4- fluorophenyl)- 1 H-imidazo 1-5 -
LY2228820; 862507-23-1;
yl]-3-(2,
LY-2228820 S1494 Selleck; BCPP000179;
2-dimethylpropyl)imidazo [4,5- BCP9000872; LY 2228820; LY-2228820
b]pyridin-2-amine; methanesulfonic acid l-[2-Methoxy-4-
JX401 C21H25N02S (methylthio)benzoyl] -4- (phenylmethyl)piperidine
2-(5-amino-6-oxo-2- phenylpyrimidin- 1 -yl)-N-
FR167653; AC1NR9VL; DNC000663;
FR167653 [( 1 S ,2S)- 1 -(5 -tert-butyl- 1,3,4- DNC001061
oxadiazo 1-2-yl)- 1 -hydro xy-3 - methylbutan-2-yl] acetamide
ML-3403; K00568a; ML3403;
4-[5-(4-fluorophenyl)-2- AC104WCF; CHEMBL111364; p38
methylsulfanyl- 1 H-imidazo 1-4-
ML-3403 MAP Kinase Inhibitor III;
yl]-N-(l- CHEBL280989; HMS3229M04;
phenylethyl)pyridin-2-amine DNC004092; HSCI1 000288
[0093] Chemical structures of the compounds of Table 2 are as follows. ARRY-797:
Figure imgf000019_0001
SB220025:
Figure imgf000020_0001
SB239063:
Figure imgf000020_0002
Figure imgf000021_0001
Figure imgf000021_0002
Figure imgf000021_0003
RWJ67657:
Figure imgf000022_0001
Figure imgf000023_0001
-21- MW01-2-069A-SRM
Figure imgf000024_0001
JX401:
Figure imgf000024_0002
SB 681323:
Figure imgf000024_0003
BMS-582949:
Figure imgf000025_0001
Figure imgf000025_0002
[0094] In some embodiments the invention provides a compound of Formula (III):
Figure imgf000025_0003
(III), wherein:
Z is O, S, or N(R10); each of R8, R9, R10, and R11 is independently H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, or alkylheterocyclyl, wherein each alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, and alkylheterocyclyl group is independently unsubstituted or substituted, or any two of R8, R9, R10, and R11 form a ring together with the atoms to which they are bound, wherein the ring is unsubstituted or substituted, or a pharmaceutically-acceptable salt or tautomer thereof.
[0095] In some embodiments, Z is N(R10).
[0096] In some embodiments, the compound of Formula (III) is a compound of Formula (IV):
Figure imgf000026_0001
wherein each of R8, R9, R10, and R11 is independently H, alkyl, alkenyl, alkynyl, alkoxy, thioether, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, or alkylheterocyclyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, thioether, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, and alkylheterocyclyl group is independently unsubstituted or substituted, or any two of R8, R9, R10, and R11 form a ring together with the atoms to which they are bound, wherein the ring is unsubstituted or substituted.
[0097] In some embodiments, R8 is H, alkyl, aryl or heterocyclyl. In some embodiments, R8 is aryl or heterocyclyl.
0098] In some embodiments, R8 is:
Figure imgf000026_0002
, wherein each R12 is independently H, OH, SH, F, CI, Br, I, amino, mono-substituted amino, di- substituted amino, alkyl, alkoxy, thioether, a carboxylic acid group, an ester group, an amido group, or a carbamoyl group.
0099] In some embodiments, R8 is:
Figure imgf000026_0003
wherein R12 is H, OH, SH, F, CI, Br, I, amino, mono-substituted amino, di-substituted amino, alkyl, alkoxy, thioether, a carboxylic acid group, an ester group, an amido group, or a carbamoyl group. R12 can be in the ortho, meta, or para position.
diments, R8 is:
Figure imgf000026_0004
wherein R12 is H, OH, SH, F, CI, Br, I, amino, mono-substituted amino, di-substituted amino, alkyl, alkoxy, thioether, a carboxylic acid group, an ester group, an amido group, or a carbamoyl group.
[00101] In some embodiments, R12 is H, OH, SH, F, CI, Br, I, amino, mono-substituted amino, or di-substituted amino. In some embodiments, R12 is H, F, CI, Br, or I. In some embodiments, R12 is F, CI, Br, or I. In some embodiments, R12 is F. In some embodiments, R12 is CI. In some embodiments, R12 is Br. In some embodiments, R12 is I.
[00102] In some embodiments, R9 is H, alkyl, aryl or heterocyclyl. In some embodiments,
R9 is aryl or heterocyclyl.
[00103] In some embodiments, R9 is:
Figure imgf000027_0001
is independently H, amino, mono-substituted amino, or di- substituted amino.
[00104] In some embodiments, R is:
Figure imgf000027_0002
wherein each R13 is independently H, amino, mono-substituted
di-substituted amino.
[00105] In some embodiments, R9 is:
Figure imgf000027_0003
wherein each R13 is independently H, amino, mono-substituted amino, or di-substituted amino.
embodiments, R9 is:
Figure imgf000027_0004
wherein R13 is H, amino, mono-substituted amino, or di-substituted ammo. [00107] In some embodiments, R13 is H or mono-substituted amino. In some embodiments, R13 is mono-substituted amino. In some embodiments, R13 is arylalkyl
13 is:
Figure imgf000028_0001
A is O, S, N, or N(R15); B is O, S, N, or N(R15); R14 is H, OH, SH, amino, mono-substituted amino, or di-substituted amino; each R15 is
independently H or alkyl; and each is independently a single or double bond.
nts, R9 is:
Figure imgf000028_0002
R15 , wherein R14 is H, OH, SH, amino, mono-substituted or di-substituted amino; and R15 is H or alkyl.
[00111] In some embodiments, R14 is amino. In some embodiments, R15 is alkyl.
[00112] In some embodiments, R9 is:
Figure imgf000028_0003
[00113] In some embodiments, R is:
Figure imgf000029_0001
, wherein R16 is H, OH, SH, amino, mono-substituted amino, di-substituted amino, alkyl, or alkoxy.
[00114] In some embodiments, R is:
Figure imgf000029_0002
wherein R16 is H, OH, SH, amino, mono-substituted amino, di-substituted amino, alkyl, or alkoxy.
[00115] In some embodiments, R16 is H, amino, or alkoxy.
[00116] In some embodiments, R10 is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, or alkylheterocyclyl, wherein each alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, and alkylheterocyclyl group is
independently unsubstituted or substituted.
[00117] In some embodiments, R10 is H, alkyl, arylalkyl, alkylaryl, or heterocyclyl.
[00118] In some embodiments, R10 is H
[00119] In some embodiments, R10 is an arylalkyl group of the formula: Ar-(CH2)n- , wherein Ar is aryl, and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, Ar is phenyl, some embodiments, n is 1, 2, or 3.
[00120] In some embodiments, R10 is:
Figure imgf000029_0003
[00121] In some embodiments, R11 is thioether. In some embodiments, R11 is SMe. [00122] In some embodiments, R11 is alkyl. In some embodiments, R11 is branched alkyl.
In some embodiments, R11 is t-butyl.
[00123] In some embodiments, R11 is alkynyl. In some embodiments, R11 is:
Figure imgf000030_0001
, wherein p is 1, 2, 3, 4, or 5. In some embodiments, p is 1. In some embodiments, p is 2.
[00124] In some embodiments, R11 is aryl.
[00125] In some embodiments, R11 is:
Figure imgf000030_0002
wherein each R17 is independently H, OH, SH, halogen, amino, mono- substituted amino, di-substituted amino, alkyl, aryl, heterocyclyl, an ester group, an alkoxy group, a thioether group, an amido group, a carbamate group, or S(0)CH3.
[00126] In some embodiments, R11 is:
Figure imgf000030_0003
, wherein R17 is H, OH, SH, halogen, amino, mono-substituted amino, di-substituted amino, alkyl, aryl, heterocyclyl, an ester group, an alkoxy group, a thioether group, an amido group, a carbamate group, or S(0)CH3.
[00127] In some embodiments, each R17 is independently H, OH, or S(0)CH3.
[00128] In some embodiments, the compound of Formula (III) is a compound of Formula
(V):
Figure imgf000031_0001
(V), wherein: ha 9 is:
Figure imgf000031_0002
wherein R13 is as defined herein,
or
Figure imgf000031_0003
wherein R16 is as defined herein; R10 is: H, Ar-(CH2)n- , wherein Ar is
phenyl and n is 1, 2, or 3,
Figure imgf000031_0004
or ; and R11 is: H, alkyl, or
wherein R17 is OH or S(0)CH3 [00129] In some embodiments: hal is F; R is:
Figure imgf000032_0001
wherein R13 is as defined herein; R10 is H; R11 is: wherein
R17 is OH or S(0)CH3.
[00130] In some embodiments, R13 is H and R17 is OH.
Figure imgf000032_0002
of Formula
O
Het' 'Aryl (VI), wherein:
Het is a heterocycle that is unsubstituted or substituted; and Aryl is an aryl group that is unsubstituted or substituted, or a pharmaceutically-acceptable salt thereof.
[00134] In some embodiments, the compound of Formula (VI) is a compound of Formula
(VII): R (VII), wherein:
R18 is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, or alkylheterocyclyl, wherein the alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, and alkylheterocyclyl group is unsubstituted or substituted; each of R19, R20, and R21 is independently H, OH, SH, halogen, amino, mono-substituted amino, di- substituted amino, alkyl, aryl, heterocyclyl, an ester group, an alkoxy group, a thioether group, an amido group, or a carbamate group; p is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and q is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
[00135] In some embodiments, p is 1, 2, or 3. In some embodiments, q is 1, 2, or 3. In some embodiments, p is 2. In some embodiments, q is 2.
[00136] In some embodiments, the compound of Formula (VI) is a compound of Formula
(VIII):
Figure imgf000033_0001
R18 is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, or alkylheterocyclyl, wherein the alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, and alkylheterocyclyl group is unsubstituted or substituted; and each of R19 and R20 is independently H, OH, SH, halogen, amino, mono-substituted amino, di- substituted amino, alkyl, aryl, heterocyclyl, an ester group, an alkoxy group, a thioether group, an amido group, or a carbamate group.
[00137] In some embodiments, R18 is H, alkyl, aryl, alkylaryl, or heterocyclyl. In some
18 19 20
embodiments, R is alkyl or alkylaryl. In some embodiments, each of R and R is independently H, OH, SH, halogen, an alkoxy group, or a thioether group. In some
embodiments, each of R19 and R20 is independently an alkoxy group or a thioether group. In some embodiments, R19 is an alkoxy group. In some embodiments, R20 is a thioether group.
[00138] In some embodiments, the compound of Formula (VI) is:
Figure imgf000034_0001
[00139] In some embodiments, the compound of Formula (VI) is SB 681323.
[00140] on-limiting examples of optional substituents include hydroxyl groups, sulfhydryl groups, halogens, amino groups, nitro groups, nitroso groups, cyano groups, azido groups, sulfoxide groups, sulfone groups, sulfonamide groups, carboxyl groups, carboxaldehyde groups, imine groups, alkyl groups, halo-alkyl groups, alkenyl groups, halo-alkenyl groups, alkynyl groups, halo-alkynyl groups, alkoxy groups, aryl groups, aryloxy groups, aralkyl groups, arylalkoxy groups, heterocyclyl groups, acyl groups, acyloxy groups, carbamate groups, amide groups, urethane groups, and ester groups.
[00141] Non-limiting examples of alkyl groups include straight, branched, and cyclic alkyl groups. Non-limiting examples of straight alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl.
[00142] Branched alkyl groups include any straight alkyl group substituted with any number of alkyl groups. Non- limiting examples of branched alkyl groups include isopropyl, isobutyl, sec-butyl, and t-butyl.
[00143] Non-limiting examples of cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptlyl, and cyclooctyl groups. Cyclic alkyl groups also include fused-, bridged-, and spiro-bicycles and higher fused-, bridged-, and spiro-systems. A cyclic alkyl group can be substituted with any number of straight, branched, or cyclic alkyl groups.
[00144] Non-limiting examples of alkenyl groups include straight, branched, and cyclic alkenyl groups. The olefin or olefins of an alkenyl group can be, for example, E, Z, cis, trans, terminal, or exo-methylene.
[00145] Non-limiting examples of alkynyl groups include straight, branched, and cyclic alkynyl groups. The triple bond of an alkylnyl group can be internal or terminal.
[00146] A halo group can be any halogen atom, for example, fluorine, chlorine, bromine, or iodine.
[00147] A halo-alkyl group can be any alkyl group substituted with any number of halogen atoms, for example, fluorine, chlorine, bromine, and iodine atoms. A halo-alkenyl group can be any alkenyl group substituted with any number of halogen atoms. A halo-alkynyl group can be any alkynyl group substituted with any number of halogen atoms.
[00148] An alkoxy group can be, for example, an oxygen atom substituted with any alkyl, alkenyl, or alkynyl group. An ether or an ether group comprises an alkoxy group. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, and isobutoxy.
[00149] An aryl group can be heterocyclic or non-heterocyclic. An aryl group can be monocyclic or polycyclic. An aryl group can be substituted with any number of substituents, for example, hydrocarbyl groups, alkyl groups, alkoxy groups, and halogen atoms. Non-limiting examples of aryl groups include phenyl, toluyl, naphthyl, pyrrolyl, pyridyl, imidazolyl, thiophenyl, and furyl.
[00150] An aryloxy group can be, for example, an oxygen atom substituted with any aryl group, such as phenoxy.
[00151] An aralkyl group can be, for example, any alkyl group substituted with any aryl group, such as benzyl.
[00152] An arylalkoxy group can be, for example, an oxygen atom substituted with any aralkyl group, such as benzyloxy.
[00153] A heterocycle can be any ring containing a ring atom that is not carbon. A heterocycle can be substituted with any number of substituents, for example, alkyl groups and halogen atoms. A heterocycle can be aromatic or non-aromatic. Non-limiting examples of heterocycles include pyrrole, pyrrolidine, pyridine, piperidine, succinamide, maleimide, morpholine, imidazole, thiophene, furan, tetrahydrofuran, pyran, and tetrahydropyran.
[00154] An acyl group can be, for example, a carbonyl group substituted with
hydrocarbyl, alkyl, hydro carbyloxy, alkoxy, aryl, aryloxy, aralkyl, arylalkoxy, or a heterocycle. Non-limiting examples of acyl include acetyl, benzoyl, benzyloxycarbonyl, phenoxycarbonyl, methoxycarbonyl, and ethoxycarbonyl.
[00155] An acyloxy group can be an oxygen atom substituted with an acyl group. An ester or an ester group comprises an acyloxy group. A non- limiting example of an acyloxy group, or an ester group, is acetate.
[00156] A carbamate group can be an oxygen atom substituted with a carbamoyl group, wherein the nitrogen atom of the carbamoyl group is unsubstituted, mono substituted, or disubstituted with one or more of hydrocarbyl, alkyl, aryl, heterocyclyl, or aralkyl. When the nitrogen atom is disubstituted, the two substituents together with the nitrogen atom can form a heterocycle. [00157] The disclosure provides the use of pharmaceutically-acceptable salts of any compound described herein. Pharmaceutically-acceptable salts include, for example, acid- addition salts and base-addition salts. The acid that is added to the compound to form an acid- addition salt can be an organic acid or an inorganic acid. A base that is added to the compound to form a base-addition salt can be an organic base or an inorganic base. In some embodiments, a pharmaceutically-acceptable salt is a metal salt. In some embodiments, a pharmaceutically- acceptable salt is an ammonium salt.
[00158] Metal salts can arise from the addition of an inorganic base to a compound of the disclosure. The inorganic base consists of a metal cation paired with a basic counterion, such as, for example, hydroxide, carbonate, bicarbonate, or phosphate. The metal can be an alkali metal, alkaline earth metal, transition metal, or main group metal. In some embodiments, the metal is lithium, sodium, potassium, cesium, cerium, magnesium, manganese, iron, calcium, strontium, cobalt, titanium, aluminum, copper, cadmium, or zinc.
[00159] In some embodiments, a metal salt is a lithium salt, a sodium salt, a potassium salt, a cesium salt, a cerium salt, a magnesium salt, a manganese salt, a iron salt, a calcium salt, a strontium salt, a cobalt salt, a titanium salt, an aluminum salt, a copper salt, a cadmium salt, or a zinc salt.
[00160] Ammonium salts can arise from the addition of ammonia or an organic amine to a compound of the disclosure. In some embodiments, the organic amine is triethyl amine, diisopropyl amine, ethanol amine, diethanol amine, triethanol amine, morpholine, N- methylmorpholine, piperidine, N-methylpiperidine, N-ethylpiperidine, dibenzylamine, piperazine, pyridine, pyrrazole, pipyrrazole, imidazole, pyrazine, or pipyrazine.
[00161] In some embodiments, an ammonium salt is a triethyl amine salt, a diisopropyl amine salt, an ethanol amine salt, a diethanol amine salt, a triethanol amine salt, a morpholine salt, an N-methylmorpholine salt, a piperidine salt, an N-methylpiperidine salt, an N- ethylpiperidine salt, a dibenzylamine salt, a piperazine salt, a pyridine salt, a pyrrazole salt, a pipyrrazole salt, an imidazole salt, a pyrazine salt, or a pipyrazine salt.
[00162] Acid addition salts can arise from the addition of an acid to a compound of the disclosure. In some embodiments, the acid is organic. In some embodiments, the acid is inorganic. In some embodiments, the acid is hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, nitrous acid, sulfuric acid, sulfurous acid, a phosphoric acid, isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbic acid, gentisinic acid, gluconic acid, glucaronic acid, saccaric acid, formic acid, benzoic acid, glutamic acid, pantothenic acid, acetic acid, propionic acid, butyric acid, fumaric acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, oxalic acid, or maleic acid.
[00163] In some embodiments, the salt is a hydrochloride salt, a hydrobromide salt, a hydroiodide salt, a nitrate salt, a nitrite salt, a sulfate salt, a sulfite salt, a phosphate salt, isonicotinate salt, a lactate salt, a salicylate salt, a tartrate salt, an ascorbate salt, a gentisinate salt, a gluconate salt, a glucaronate salt, a saccarate salt, a formate salt, a benzoate salt, a glutamate salt, a pantothenate salt, an acetate salt, a propionate salt, a butyrate salt, a fumarate salt, a succinate salt, a methanesulfonate (mesylate) salt, an ethanesulfonate salt, a benzenesulfonate salt, a p-toluenesulfonate salt, a citrate salt, an oxalate salt , or a maleate salt.
Pharmaceutical Compositions.
[00164] A pharmaceutical composition of the disclosure can be a combination of any pharmaceutical compounds described herein with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients. The pharmaceutical composition facilitates administration of the compound to an organism. Pharmaceutical compositions can be administered in therapeutically-effective amounts as pharmaceutical compositions by any form and route known in the art including, for example, intravenous, subcutaneous, intramuscular, oral, rectal, aerosol, parenteral, ophthalmic, pulmonary, transdermal, vaginal, otic, nasal, and topical administration.
[00165] A pharmaceutical composition can be administered in a local or systemic manner, for example, via injection of the compound directly into an organ, optionally in a depot or sustained release formulation. Pharmaceutical compositions can be provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation. A rapid release form can provide an immediate release. An extended release formulation can provide a controlled release or a sustained delayed release.
[00166] For oral administration, pharmaceutical compositions can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers or excipients well known in the art. Such carriers can be used to formulate tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions and the like, for oral ingestion by a subject.
[00167] Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Cores can be provided with suitable coatings. For this purpose, concentrated sugar solutions can be used, which may optionally contain an excipient such as gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments can be added to the tablets or dragee coatings, for example, for identification or to characterize different combinations of active compound doses.
[00168] Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. In some embodiments, the capsule comprises a hard gelatin capsule comprising one or more of pharmaceutical, bovine, and plant gelatins. A gelatin can be alkaline processed. The push- fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. Stabilizers can be added. All formulations for oral administration are provided in dosages suitable for such administration.
[00169] For buccal or sublingual administration, the compositions can be tablets, lozenges, or gels.
[00170] Parental injections can be formulated for bolus injection or continuous infusion.
The pharmaceutical compositions can be in a form suitable for parenteral injection as a sterile suspension, solution or emulsion in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Suspensions of the active compounds can be prepared as oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions can contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. The suspension can also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, the active ingredient can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen- free water, before use.
[00171] The active compounds can be administered topically and can be formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams, and ointments. Such pharmaceutical compositions can contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
[00172] Formulations suitable for transdermal administration of the active compounds can employ transdermal delivery devices and transdermal delivery patches, and can be lipophilic emulsions or buffered aqueous solutions, dissolved and/or dispersed in a polymer or an adhesive. Such patches may be constructed for continuous, pulsatile, or on demand delivery of
pharmaceutical compounds. Transdermal delivery can be accomplished by means of
iontophoretic patches and the like. Additionally, transdermal patches can provide controlled delivery. The rate of absorption can be slowed by using rate-controlling membranes or by trapping the compound within a polymer matrix or gel. Conversely, absorption enhancers can be used to increase absorption. An absorption enhancer or carrier can include absorbable pharmaceutically acceptable solvents to assist passage through the skin. For example, transdermal devices can be in the form of a bandage comprising a backing member, a reservoir containing compounds and carriers, a rate controlling barrier to deliver the compounds to the skin of the subject at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
[00173] For administration by inhalation, the active compounds can be in a form as an aerosol, a mist, or a powder. Pharmaceutical compositions are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator can be formulated containing a powder mix of the compounds and a suitable powder base such as lactose or starch.
[00174] The compounds can also be formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and the like. In suppository forms of the compositions, a low-melting wax such as a mixture of fatty acid glycerides, optionally in combination with cocoa butter, is first melted.
[00175] In practicing the methods of treatment or use provided herein, therapeutically- effective amounts of the compounds described herein are administered in pharmaceutical compositions to a subject having a disease or condition to be treated. In some embodiments, the subject is a mammal such as a human. A therapeutically-effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compounds used, and other factors. The compounds can be used singly or in combination with one or more therapeutic agents as components of mixtures.
[00176] Pharmaceutical compositions can be formulated using one or more
physiologically-acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compounds into preparations that can be used pharmaceutically.
Formulation can be modified depending upon the route of administration chosen.
Pharmaceutical compositions comprising a compounds described herein can be manufactured in a conventional manner, for example, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.
[00177] The pharmaceutical compositions can include at least one pharmaceutically acceptable carrier, diluent, or excipient and compounds described herein as free-base or pharmaceutically-acceptable salt form. The methods and pharmaceutical compositions described herein include the use crystalline forms (also known as polymorphs), and active metabolites of these compounds having the same type of activity.
[00178] Methods for the preparation of compositions comprising the compounds described herein include formulating the compounds with one or more inert, pharmaceutically- acceptable excipients or carriers to form a solid, semi-solid, or liquid composition. Solid compositions include, for example, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include, for example, solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein. Semi-solid compositions include, for example, gels, suspensions and creams. The compositions can be in liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions can also contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and other
pharmaceutically-acceptable additives.
[00179] Compounds can be delivered via liposomal technology. The use of liposomes as drug carriers can increase the therapeutic index of the compounds. Liposomes are composed of natural phospholipids, and can contain mixed lipid chains with surfactant properties (e.g., egg phosphatidylethanolamine). A liposome design can employ surface ligands for attaching to unhealthy tissue. Non-limiting examples of liposomes include the multilamellar vesicle (MLV), the small unilamellar vesicle (SUV), and the large unilamellar vesicle (LUV). Liposomal physico chemical properties can be modulated to optimize penetration through biological barriers and retention at the site of administration, and to prevent premature degradation and toxicity to non-target tissues. Optimal liposomal properties depend on the administration route: large-sized liposomes show good retention upon local injection, small-sized liposomes are better suited to achieve passive targeting. PEGylation reduces the uptake of the liposomes by liver and spleen, and increases the circulation time, resulting in increased localization at the inflamed site due to the enhanced permeability and retention (EPR) effect. Additionally, liposomal surfaces can be modified to achieve selective delivery of the encapsulated drug to specific target cells. Non- limiting examples of targeting ligands include monoclonal antibodies, vitamins, peptides, and polysaccharides specific for receptors concentrated on the surface of cells associated with the disease.
[00180] Non-limiting examples of dosage forms suitable for use in the disclosure include feed, food, pellet, lozenge, liquid, elixir, aerosol, inhalant, spray, powder, tablet, pill, capsule, gel, geltab, nanosuspension, nanoparticle, microgel, suppository troches, aqueous or oily suspensions, ointment, patch, lotion, dentifrice, emulsion, creams, drops, dispersible powders or granules, emulsion in hard or soft gel capsules, syrups, phytoceuticals, nutraceuticals, and any combination thereof.
[00181] Non-limiting examples of pharmaceutically-acceptable excipients suitable for use in the disclosure include granulating agents, binding agents, lubricating agents, disintegrating agents, sweetening agents, glidants, anti-adherents, anti-static agents, surfactants, anti-oxidants, gums, coating agents, coloring agents, flavouring agents, coating agents, plasticizers, preservatives, suspending agents, emulsifying agents, plant cellulosic material and
spheronization agents, and any combination thereof.
[00182] A composition of the disclosure can be, for example, an immediate release form or a controlled release formulation. An immediate release formulation can be formulated to allow the compounds to act rapidly. Non-limiting examples of immediate release formulations include readily dissolvable formulations. A controlled release formulation can be a pharmaceutical formulation that has been adapted such that drug release rates and drug release profiles can be matched to physiological and chronotherapeutic requirements or, alternatively, has been formulated to effect release of a drug at a programmed rate. Non-limiting examples of controlled release formulations include granules, delayed release granules, hydrogels (e.g., of synthetic or natural origin), other gelling agents (e.g., gel-forming dietary fibers), matrix-based formulations (e.g., formulations comprising a polymeric material having at least one active ingredient dispersed through), granules within a matrix, polymeric mixtures, granular masses, and the like.
[00183] Compositions of the disclosure can be delivered via a time-controlled delivery system. An example of a suitable time-controlled delivery system is the PULSINCAP® system, or a variant thereof. The time-controlled delivery system can further comprise pH-dependent systems, microbially-triggered delivery systems, or a combination thereof. The time-controlled system may comprise a water insoluble capsule body enclosing a drug reservoir. The capsule body can be closed at one end with a hydrogel plug. The hydrogel plug can comprise swellable polymers, erodible compressed polymers, congealed melted polymers, enzymatically-controlled erodible polymers, or a combination thereof. The swellable polymers can include
polymethacrylates. Non-limiting examples of erodible compressed polymers include hydroxypropyl methylcellulose, polyvinyl alcohol, polyvinyl acetate, polyethylene oxide, and combinations thereof. Non-limiting examples of congealed melted polymers include saturated polyglycolated glycerides, glyceryl monooleate, and combinations thereof. Non-limiting examples of enzymatically-controlled erodible polymers include polysaccharides; amylose; guar gum; pectin; chitosan; inulin; cyclodextrin; chondroitin sulphate; dextrans; locust bean gum; arabinogalactan; chondroitin sulfate; xylan; calcium pectinate; pectin/chitosan mixtures;
amidated pectin; and combinations thereof.
[00184] The time-controlled delivery system can comprise a capsule, which further comprises an organic acid. The organic acid can be filled into the body of a hard gelatine capsule. The capsule can be coated with multiple layers of polymers. The capsule can be coated first with an acid soluble polymer, such as EUDRAGIT® E, then with a hydrophilic polymer, such as hydroxypropyl methylcellulose, and finally with an enteric coating, such as
EUDRAGIT® L.
[00185] An additional example of a suitable time-controlled delivery system is the
CHRONOTROPIC® system, or a variant thereof, which comprises a drug core that is coated with hydroxypropyl methylcellulose and an outer enteric film.
[00186] An additional example of a suitable time-controlled delivery system is the
CODES™ system, or a variant thereof. The time-controlled delivery system can comprise a capsule body, which can house, for example, a drug-containing tablet, an erodible tablet, a swelling expulsion excipient, or any combination thereof. The capsule can comprise an ethyl cellulose coat. The time-controlled delivery system can comprise two different sized capsules, one inside the other. The space between the capsules can comprise a hydrophilic polymer. The drug-containing core canay be housed within the inner capsule. The drug delivery system can comprise an impermeable shell, a drug-containing core, and erodible outer layers at each open end. When the outer layers erode, the drug is released.
[00187] Examples of suitable multiparticulate drug delivery systems include
DIFFUCAPS®, DIFFUTAB®, ORBEXA®, EURAND MINITABS®, MICROCAPS®, and variants thereof. The drug delivery system can comprise multiparticulate beads, which are comprised of multiple layers of the drug compound, excipients, and release-controlling polymers. The multiparticulate beads can comprise an organic acid or alkaline buffer. The multiparticulate beads can comprise a solid solution of the drug compound and crystallization inhibitor. The drug delivery system can comprise a matrix tablet containing water-soluble particles and the drug compound. The matrix tablet can further comprise hydrophilic and hydrophobic polymers. In some multiparticulate delivery systems, particles in the micron size range are used. In some multiparticulate delivery systems, nanoparticle colloidal carriers composed of natural or synthetic polymers are used.
[00188] In some embodiments, a controlled release formulation is a delayed release form.
A delayed release form can be formulated to delay a compound's action for an extended period of time. A delayed release form can be formulated to delay the release of an effective dose of one or more compounds, for example, for about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, or about 24 hours.
[00189] A controlled release formulation can be a sustained release form. A sustained release form can be formulated to sustain, for example, the compound's action over an extended period of time. A sustained release form can be formulated to provide an effective dose of any compound described herein (e.g., provide a physiologically-effective blood profile) over about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, or about 24 hours.
[00190] A tablet providing a sustained or controlled release can comprise a first layer containing one or two of the compounds described herein, and a tablet core containing one or two other compounds. The core can have a delayed or sustained dissolution rate. Other exemplary embodiments can include a barrier between the first layer and core, to limit drug release from the surface of the core. Barriers can prevent dissolution of the core when the pharmaceutical formulation is first exposed to gastric fluid. For example, a barrier can comprise a disintegrant, a dissolution-retarding coating (e.g., a polymeric material, for example, an enteric polymer such as a Eudragit polymer), or a hydrophobic coating or film, and can be selectively soluble in either the stomach or intestinal fluids. Such barriers permit the compounds to leach out slowly. The barriers can cover substantially the whole surface of the core.
[00191] Non-limiting examples of pharmaceutically-acceptable excipients can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington 's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkinsl999), each of which is incorporated by reference in its entirety.
Dosing.
[00192] Pharmaceutical compositions described herein can be in unit dosage forms suitable for single administration of precise dosages. In unit dosage form, the formulation is divided into unit doses containing appropriate quantities of one or more compounds. The unit dosage can be in the form of a package containing discrete quantities of the formulation. Non- limiting examples are packaged tablets or capsules, and powders in vials or ampoules. Aqueous suspension compositions can be packaged in single-dose non-reclosable containers. Multiple- dose reclosable containers can be used, for example, in combination with a preservative.
Formulations for parenteral injection can be presented in unit dosage form, for example, in ampoules, or in multi-dose containers with a preservative.
[00193] A compound described herein can be present in a composition in a range of from about 1 mg to about 2000 mg; from about 100 mg to about 2000 mg; from about 10 mg to about 2000 mg; from about 5 mg to about 1000 mg, from about 10 mg to about 500 mg, from about 50 mg to about 250 mg, from about 100 mg to about 200 mg, from about 1 mg to about 50 mg, from about 50 mg to about 100 mg, from about 100 mg to about 150 mg, from about 150 mg to about 200 mg, from about 200 mg to about 250 mg, from about 250 mg to about 300 mg, from about 300 mg to about 350 mg, from about 350 mg to about 400 mg, from about 400 mg to about 450 mg, from about 450 mg to about 500 mg, from about 500 mg to about 550 mg, from about 550 mg to about 600 mg, from about 600 mg to about 650 mg, from about 650 mg to about 700 mg, from about 700 mg to about 750 mg, from about 750 mg to about 800 mg, from about 800 mg to about 850 mg, from about 850 mg to about 900 mg, from about 900 mg to about 950 mg, or from about 950 mg to about 1000 mg.
[00194] A compound described herein can be present in a composition in an amount of about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, or about 2000 mg.
[00195] In some embodiments, a dose can be expressed in terms of an amount of the drug divided by the mass of the subject, for example, miligrams of drug per kilograms of subject body mass. In some embodiments, CW178 is present in a composition in an amount ranging from about 250 mg/kg to about 2000 mg/kg, about 10 mg/kg to about 800 mg/kg, about 50 mg/kg to about 400 mg/kg, about 100 mg/kg to about 300 mg/kg, or about 150 mg/kg to about 200 mg/kg. In some embodiments, CW229 is present in a composition in an amount ranging from about 10 mg/kg to about 300 mg/kg, about 2 mg/kg to about 200 mg/kg, about 3 mg/kg to about 100 mg/kg, about 5 mg/kg to about 75 mg/kg, about 10 mg/kg to about 50 mg/kg or about 20 mg/kg to about 40 mg/kg.
[00196] In some embodiments, a composition comprises from about 100 mg to about 2000 mg of CW178, from about 3 mg to about 100 mg of CW229.
[00197] In some embodiments, a compound described herein is present in a composition in an amount that is a fraction or percentage of the maximum tolerated amount. The maximum tolerated amount can be as determined in a subject, such as a mouse or human. The fraction can be expressed as a ratio of the amount present in the composition divided by the maximum tolerated dose. The ratio can be from about 1/20 to about 1/1. The ratio can be about 1/20, about 1/19, about 1/18, about 1/17, about 1/16, about 1/15, about 1/14, about 1/13, about 1/12, about 1/11, about 1/10, about 1/9, about 1/8, about 1/7, about 1/6, about 1/5, about 1/4, about 1/3, about 1/2, or about 1/1. The ratio can be 1/20, 1/19, 1/18, 1/17, 1/16, 1/15, 1/14, 1/13, 1/12, 1/11, 1/10, 1/9, 1/8, 1/7, 1/6, 1/5, 1/4, 1/3, 1/2, or 1/1. The ratio can be about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%. The ratio can be in a range from about 5% to about 100%, from about 10% to about 100%), from about 5%> to about 80%>, from about 10%> to about 80%>, from about 5%> to about 60%), from about 10%> to about 60%>, from about 5%> to about 50%>, from about 10%> to about 50%), from about 5%> to about 40%>, from about 10%> to about 40%>, from about 5%> to about 20%, or from about 10% to about 20%.
[00198] For example, the maximum tolerated dose of Metformin is 2000 mg in man. The maximum tolerated dose of SB681323 is 25 mg in man.
[00199] The foregoing ranges are merely suggestive. Dosages can be altered depending on a number of variables, including, for example, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.
[00200] A dose can be modulated to achieve a desired pharmacokinetic or
pharmacodynamics profile, such as a desired or effective blood profile, as described herein. Pharmacokinetic and Pharmacodynamic Measurements.
[00201] Pharmacokinetic and pharmacodynamic data can be obtained by techniques known in the art. Appropriate pharmacokinetic and pharmacodynamic profile components describing a particular composition can vary due to the inherent variation in pharmacokinetic and pharmacodynamic parameters of drug metabolism in human subjects. Pharmacokinetic and pharmacodynamic profiles can be based on the determination of the mean parameters of a group of subjects. The group of subjects includes any reasonable number of subjects suitable for determining a representative mean, for example, 5 subjects, 10 subjects, 16 subjects, 20 subjects, 25 subjects, 30 subjects, 35 subjects, or more. The mean is determined by calculating the average of all subject's measurements for each parameter measured.
[00202] The pharmacokinetic parameters can be any parameters suitable for describing a compound disclosed herein. For example, the Cmax can be not less than about 100 ng/mL; not less than about 200 ng/mL; not less than about 300 ng/mL; not less than about 400 ng/mL; not less than about 500 ng/mL; not less than about 600 ng/mL; not less than about 700 ng/mL; not less than about 800 ng/mL; not less than about 900 ng/mL; not less than about 1000 ng/mL; not less than about 1250 ng/mL; not less than about 1500 ng/mL; not less than about 1750 ng/mL; not less than about 2000 ng/mL; or any other Cmax appropriate for describing a pharmacokinetic profile of a compound described herein.
[00203] The Tmax of a compound described herein can be, for example, not greater than about 0.5 hours, not greater than about 1.0 hours, not greater than about 1.5 hours, not greater than about 2.0 hours, not greater than about 2.5 hours, not greater than about 3.0 hours, or any other Tmax appropriate for describing a pharmacokinetic profile of a compound described herein.
[00204] The AU o-inf) of a compound described herein can be, for example, not less than about 250 ng»hr/mL, not less than about 500 ng»hr/mL, not less than about 1000 ng»hr/mL, not less than about 1500 ng»hr/mL, not less than about 2000 ng»hr/mL, not less than about 3000 ng»hr/mL, not less than about 3500 ng»hr/mL, not less than about 4000 ng»hr/mL, not less than about 5000 ng»hr/mL, not less than about 6000 ng»hr/mL, not less than about 7000 ng»hr/mL, not less than about 8000 ng»hr/mL, not less than about 9000 ng»hr/mL, or any other AU o-inf) appropriate for describing a pharmacokinetic profile of a compound described herein.
[00205] The plasma concentration of a compound described herein about one hour after administration can be, for example, not less than about 25 ng/mL, not less than about 50 ng/mL, not less than about 75 ng/mL, not less than about 100 ng/mL, not less than about 150 ng/mL, not less than about 200 ng/mL, not less than about 300 ng/mL, not less than about 400 ng/mL, not less than about 500 ng/mL, not less than about 600 ng/mL, not less than about 700 ng/mL, not less than about 800 ng/mL, not less than about 900 ng/mL, not less than about 1000 ng/mL, not less than about 1200 ng/mL, or any other plasma concentration of a compound described herein.
[00206] The pharmacodynamic parameters can be any parameters suitable for describing compositions of the disclosure. For example, the pharmacodynamic profile can exhibit decreases in viability phenotype for the tumor cells or tumor size reduction in tumor cell lines or xenograft studies, for example, about 24 hours, about 48 hours, about 72 hours, or 1 week.
[00207] For example, for Metformin, the Tmax is 1.2 hours; the Tl/2 is 13 hours (with a peak at 17.5 hours for an active metabolite), and AUC 0-24 hr 26,811 +- 7055 ng.hr/ml with 2000mg q.d. after dinner .The Cmax is 0.925 μg/mL (with a peak at 0.115 for an active metabolite).
[00208] For SB681323, the Tmax is 0.75 hours, the Tl/2 is 10 hours, Cmax is 33 ng/ml with a dosing of 7.5 mg/day. AUC 0-24 firs at the same dosing of 7.5 mg/day is 125 ng.hr/ml.
Physicochemical Properties & Mechanism of Action of a representative example of CW178.
[00209] Example Compound Name: Metformin.
[00210] Drug Bank Accession No: DB00331 (APRD01099).
[00211] Type: Small Molecule inhibitor or AMPK activator.
[00212] Description: A biguanide hypoglycemic agent used in the treatment of non- insulin-dependent diabetes mellitus not responding to dietary modification. Metformin improves glycemic control by improving insulin sensitivity and decreasing intestinal absorption of glucose. Metformin acts by increasing the sensitivity of liver, muscle, fat, and other tissues to the uptake and effects of insulin. These actions lower the level of sugar in the blood.
[00213] Unlike glucose-lowering drugs of the sulfonylurea class, for example glyburide
(Micronase; DiaBeta) or glipizide (Glucotrol), metformin does not increase the concentration of insulin in the blood and, therefore, does not cause excessively low blood glucose levels
(hypoglycemia) when used alone. In scientific studies, metformin reduced the complications of diabetes such as heart disease, blindness and kidney disease. Metformin was approved by the FDA in December 1994.
[00214] Brand names: Apo-Metformin TM; Fortamet TM; Gen-Metformin TM;
Glucophage TM; Glucophage XR TM; Glycon TM; Novo -Metformin TM; Nu-Metformin TM; Riomet TM.
[00215] Chemical Formula: C4H11N5.
[00216] IUPAC name: l-carbamimidamido-N,N-dimethylmethanimidamide. [00217] Indication: For use as an adjunct to diet and exercise to improve glycemic control in adult patients (18 years and older) with type 2 diabetes.
[00218] Mechanism of action: Metformin's pharmacologic mechanisms of action are different from other classes of oral antihyperglycemic agents. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. These effects are mediated by the initial activation by Metformin of AMP-activated protein kinase (AMPK), a liver enzyme that plays an important role in insulin signaling, whole body energy balance, and the metabolism of glucose and fats. Activation of AMPK is required for metformin's inhibitory effect on the production of glucose by liver cells. AMPK causes GLUT4 deployment to the plasma membrane, resulting in insulin-independent glucose uptake.
[00219] Absorption: Absorbed over 6 hours, bioavailability is 50 to 60% under fasting conditions. Food delays absorption.
[00220] Metabolism: Metformin is not metabolized.
[00221] Half life: 6.2 hours.
[00222] Route of elimination: Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) or biliary excretion.
[00223] In some embodiments, an activator of AMPK can be the compound Metformin.
In some embodiments, Metformin or a salt thereof is crystalline. Metformin hydrochloride, a derivative salt of Metformin, can be freely soluble in water, slightly soluble in alcohols, and insoluble in acetone, ether, chloroform, and methylene chloride.
[00224] Metformin or a salt thereof can be well-absorbed with mean absolute
bioavailability of 50% to 60%, with maximum levels achieved within 7 hours of dosing.
Metformin is negligibly bound to plasma proteins.
[00225] Side effects of Metformin therapy include, for example, acidosis, nausea and vomiting.
Physicochemical Properties & Mechanism of Action of a representative example of CW229.
[00226] Example Compound Name: SB681323.
[00227] Type: Small Molecule inhibitor.
[00228] Description: SB-681323 is Potent and selective p38 MAPK inhibitor. SB-681323 is known to inhibit P38 alpha and beta.
[00229] Chemical Formula: C23H21 F3N403. [00230] IUPAC NAME: 8-(2,6-difluorophenyl)-2-(l,3-dihydroxypropan-2-ylamino)-4-(4- fluoro-2-methylphenyl)pyrido[2,3-d]pyrimidin-7-one.
[00231] Indication: SB-681323 is relevant in treatment of Coronary Heart Disease,
Rheumatoid Arthritis, and Chronic Obstructive Pulmonary Disease.
[00232] Mechanism of action: SB-681323 is a potent p38 MAPK alpha inhibitor. p38 mitogen-activated protein kinase (MAPK) is involved in the regulation and synthesis of inflammatory mediators Hence SB-681323 is used as potential p38 MAPK inhibitor that potentially suppresses inflammation in COPD.
[00233] Half life: Terminal Half Life is 10 hours.
[00234] In some embodiments, an inhibitor of P38-MAPK can be the compound
SB681323. Pharmaceutical compositions formulated with SB681323 can be called, for example, DCL000517, GW681323, D09602, UNII-Q3238VQW0N, or Dilmapimod. In some
embodiments, SB681323 or a salt thereof is crystalline.
[00235] SB681323 or a salt thereof can be well-absorbed with mean absolute
bioavailability of about 50% with maximum levels achieved within 0.75 hours of dosing.
[00236] Side effects of SB681323 therapy include, for example, cardiac and vascular disorders, headache, hemoglobin decrease, and Lower Respiratory tract infection.
Cancer and Associated Conditions and Methods of Treatment.
[00237] In some embodiments, the disclosure provides a process for preparing a composition, the composition comprising one or more compounds, wherein the compounds are CW178 and CW229, wherein the composition optionally further comprises a pharmaceutically- acceptable excipient, wherein the process comprises the step of combining the compounds and the optional excipient in any order thereof.
[00238] The disclosure described herein provides therapeutic methods for the treatment of cancer and associated conditions, and combinations thereof.
[00239] In some embodiments, the invention provides a method for treating a subject having or suspected of having a condition and/or a mutation, wherein the condition is, for example, a solid tumor such as lung cancer, colorectal cancer, glioblastoma, or any combination thereof.
[00240] In some embodiments, the invention provides a method for treating a subject having or suspected of having: a mutation(s) in the BRAF, EGFR, KRAS, beta-catenin,
CDKN2A, P13KCA, APC, or SMAD4 genes or family members, or any combination thereof, the method comprising administering to the subject a combination of: a) a therapeutically- effective amount of an AMPK activator; and b) a therapeutically-effective amount of an inhibitor of P38-MAPK activity, wherein the administration uses one or a plurality of dosage forms, each dosage form comprising one or more inhibitors, and wherein each dosage form optionally further comprises a pharmaceutically-acceptable excipient.
[00241] In some embodiments, the invention provides a use of a combination of compounds in the preparation of a medicament for the treatment of cancer and associated conditions, the compounds comprising: an activator of AMPK and an inhibitor of P38-MAPK activity.
[00242] In some embodiments, the invention provides a composition for use in treating a cancer in a subject, the composition comprising: a) i) an AMPK activator; and ii) an inhibitor of P38-MAPK activity; and b) a pharmaceutically-acceptable excipient, wherein the composition is a unit dosage form.
[00243] In some embodiments, the invention provides a use of a composition in formulating a medicament for treating a cancer in a subject, the composition comprising: a) i) an AMPK activator; and ii) an inhibitor of P38-MAPK activity; and b) a pharmaceutically- acceptable excipient, wherein the composition is a unit dosage form.
[00244] In some embodiments the invention provides a use of a combination of compounds in the preparation of a kit for the treatment of cancer and associated conditions, the compounds comprising: an activator of AMPK and an inhibitor of P38-MAPK activity.
[00245] In some embodiments, the invention provides a kit for use in treating a cancer in a subject, the composition comprising: a) i) an AMPK activator; and ii) an inhibitor of P38-MAPK activity; and b) a pharmaceutically-acceptable excipient, wherein the composition is a unit dosage form.
[00246] In some embodiments, the invention provides a use of a composition in formulating a medicament for treating a cancer in a subject, the composition comprising: a) i) an AMPK activator; and ii) an inhibitor of P38-MAPK activity; and b) a pharmaceutically- acceptable excipient, wherein the composition is a unit dosage form.
[00247] Pharmaceutical compositions containing compounds described herein can be administered for prophylactic and/or therapeutic treatments. In therapeutic applications, the compositions are administered to a subject already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition, or to cure, heal, improve, or ameliorate the condition itself. Amounts effective for this use can vary based on the severity and course of the disease or condition, previous therapy, the subject's health status, weight, and response to the drugs, and the judgment of the treating physician. Pharmaceutically-acceptable amounts can be determined by routine experimentation, for example, by a dose escalation clinical trial.
[00248] Multiple therapeutic agents can be administered in any order or simultaneously. If simultaneously, the multiple therapeutic agents can be provided in a single, unified form, or in multiple forms, for example, as multiple separate pills. The compounds can be packed together or separately, in a single package or in a plurality of packages. One or all of the therapeutic agents can be given in multiple doses. If not simultaneous, the timing between the multiple doses may vary to as much as about a month.
[00249] In some embodiments, compounds of the disclosure are administered sequentially at a time interval. The time interval can range from about 1 second to about 600 minutes.
[00250] Compounds and compositions of the disclosure can be packaged as a kit. In some embodiments, a kit includes written instructions on the use of the compounds and compositions. The instructions can provide information on the identity of the therapeutic agent(s), modes of administration, or the indications for which the therapeutic agent(s) can be used.
[00251] In some embodiments, therapeutics are combined with genetic or genomic testing to determine whether that individual is a carrier of a mutant gene that is known to be correlated with certain diseases or conditions. A personalized medicine approach can be used to provide companion diagnostic tests to discover a subject's predisposition to certain conditions and susceptibility to therapy. For example, a subject who is an anti-EGFR non-responder could be identified via companion diagnostics. The companion diagnostic test can be performed on the patient's tumor sample. Instructions on the use of a companion diagnostic test can be provided on written material packaged with a compound, composition, or kit of the disclosure. The written material can be, for example, a label. The written material can suggest conditions or genetic features relevant to cancer or amenable to intervention by the compounds of the disclosure. The instructions provide the subject and the supervising physician with the best guidance for achieving the optimal clinical outcome from the administration of the therapy.
[00252] Compounds described herein can be administered before, during, or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound can vary. For example, the compounds can be used as a prophylactic and can be administered continuously to subjects with a propensity to conditions or diseases in order to prevent the occurrence of the disease or condition. The compounds and compositions can be administered to a subject during or as soon as possible after the onset of the symptoms. The administration of the compounds can be initiated within the first 48 hours of the onset of the symptoms, within the first 24 hours of the onset of the symptoms, within the first 6 hours of the onset of the symptoms, or within 3 hours of the onset of the symptoms. The initial administration can be via any route practical, such as by any route described herein using any formulation described herein. A compound can be administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease, such as, for example, from about 1 month to about 3 months. The length of treatment can vary for each subject, and the length can be determined using the known criteria.
Malignancies harboring KRAS and BRAF mutations.
[00253] In some embodiments, the invention provides a treatment for solid tumors such as lung cancer, colorectal cancer, pancreatic cancer, glioblastoma, or any condition, or combination of conditions, where the cancer harbors mutations or variants of the KRAS and BRAF genes. Mutations in KRAS and BRAF have been found in a large number of colon and lung
malignancies. Almost 40% of colorectal tumors harbor KRAS mutations, and more than 60% of non-small cell lung tumors harbor KRAS mutations.
[00254] KRAS, also known as Kirsten rat sarcoma viral oncogene homolog, is present in a significant proportion of colorectal and NSCLC cancers. KRAS protein is a GTPase that plays an important role in cell growth, and in the progression of cancer. The KRAS gene can be altered (mutated), or it can be present in a wild type form within cancer cells. Presence of mutated KRAS can be an indicator of a more aggressive tumor. If the KRAS gene is mutated, then currently-available anti-EGFR therapies, such as Erbitux and Erlotinib (Tarceva), are not effective and should not be used in the treatment of those cancers.
[00255] In some embodiments, the invention provides a drug and a treatment for colon and lung tumors with known mutations in the KRAS gene. Although colorectal cancer patients harboring wild-type copies of the KRAS gene (non-mutated KRAS) have a better response to available anti-EGFR therapies, such as Erbitux, approximately 50% of the colorectal cancer KRAS wild-type population do not respond to anti-EGFR therapies owing to the presence of BRAF or other mutations. In the context of cell signaling pathways, KRAS is located downstream of EGFR, and upstream of the MAPK signaling pathway, which drives cellular proliferation, and survival endpoints. Therefore, the commonly-found KRAS mutations in colon and lung cancer bypass the effects of EGFR drugs treatments targeting the EGFR receptors, and can require further treatment such as the treatment provided by the invention.
[00256] In some embodiments, the invention provides a drug and a treatment for colon and lung tumors with known mutations in the BRAF gene. The BRAF gene makes a protein called B-RAF, which is involved in cell growth signaling. A mutated version of the gene can increase the growth and spread of colorectal cancer cells. This mutation in the BRAF gene has been shown to make colorectal cancers resistant to anti-EGFR therapies such as Erbitux.
Patients with this mutation in their tumors are therefore considered unlikely to benefit from anti- EGFR therapies.
Virtual Tumor Based In-Vivo aligned studies of Therapies of the Disclosure.
[00257] The compositions of the disclosure were analyzed on a virtual tumor cell system designed to represent the disease state, and customized to match a specific molecular profile of specific cancer baselines. These experiments have also been validated with in-vitro data as depicted in Examples 1 to 8.
[00258] The baselines selected for the virtual experiments included:
a) H1299 human lung cancer cell line harboring the following mutations: KRAS over- activation, PTEN deletion, CDKN2A deletion, and P53 deletion;
b) HCT116 human colon cancer cell line harboring the following mutations: KRAS over- activation, PIK3CA over-expression, B-catenin over-expression; CDKN2A deletion, COX2 deletion, and BCL2 over-expression; and
c) MDA-MB-231 human breast cancer cell line harboring the following mutations: KRAS over-activation, BRAF over-expression, CDKN2A deletion, Integrin over-expression, annexin 1 over-expression, and P53 mutation.
[00259] In the virtual experiments, the system was first simulated with the respective oncogenic mutations aligned to the specific profiles, and then cultured for a minimum of about 35 hours of simulation time. The culture time was selected to allow the system to attain the severe oncogenic state through activation of autocrine and paracrine pathway loops affecting all oncogenic mediators like growth factors, kinases, and transcription factors. After about 35 hours of simulation time, a system customized to the above tumor profiles was created.
[00260] As used in the virtual co-cultures, and throughout Figures (1 - 27) and references to the same: CW178 is Metformin (AMPK activator); CW229 is SB202190 (P38 MAPK inhibitor); and CWG89 is a combination of Metformin and SB202190. The Figures reflect the simulated dosing for the virtual experiments.
[00261] The drug compounds CW178 and CW229 were administered concomitantly to the
Virtual Tumor cell, and the cells were cultured for a minimum of about 18-20 hours of simulation time. The drug administration was performed at multiple dosage ratios across an array of samples for each drug. The effect of the multiple dosage ratios was evaluated after about 18-20 hours of culture by assaying the extent of decrease/increase in the tumor cell survival, apoptosis, and proliferation markers. The major markers assayed include CCND1 and CDK-Cyclin complexes responsible for cell proliferation. Other proteins including BCL2, BIRC5, BAX, CASP3, and PARPl cleaved were assayed to determine their effect on tumor cell survival and apoptosis. Other vital biomarkers including VEGFA were assayed to estimate the levels of angiogenesis.
[00262] Based on the assayed biomarkers, an overall viability score was calculated as a ratio of survival/apoptosis.
[00263] "Viability" is a scale to measure change in tumorogenic symptoms. A reduction greater than 30% in tumorogenic symptoms is considered moderately effective and a reduction greater than 50% is considered an effective therapy.
[00264] The combinations of compounds described herein can provide therapeutic benefits at low dosage, including synergistic benefits. Figure 1 illustrates the scientific rationale underlying the present disclosure, along with illustration of the biochemical targets implicated in the relevant oncogenic pathways. Figure 1 illustrates the activation of the AMP-activated protein kinase (AMPK) cell signaling pathway by CW178, and inhibition of cell signaling downstream of P38 mitogen-activated protein kinases by CW229.
[00265] Figure 2 and 3 illustrate the computer-simulated dose response curves for the HCTl 16, MDA-MB-231, and HI 299 cell lines treated with individual drugs CW178 and CW229 respectively.
[00266] Figures 4a, 4b, and 4c illustrate the simulated efficacies of individual drugs, and combinations thereof, in terms of viability on the selected tumor profiles. The individual bars represent the efficacy of CW178, CW229, and CWG89. In combination, the CWG89 bar, the IC30 concentration of each drug was used. The percent change seen in viability in the profiles is been tabulated below.
Figure imgf000054_0001
Tabulation of Figure 4b Data
Drug % Change in Viability in HCT116
CW178 -28.55
CW229 -32.04
CWG89 -47.33
Tabulation of Figure 4c Data
Drug % Change in Viability in MDA-MB-231
CW178 -34.41
CW229 -38.24
CWG89 -52.97
[00267] The results illustrated in Figures 4a, b, and c indicate that CWG89 exhibits enhanced efficacy when compared to CW178 and CW229 individually, as CWG89 causes a higher reduction in viability than the individual drugs.
[00268] Figures 5a, b, c, and d illustrate the effect of CWG89 on key bio-markers in the selected tumor profiles. The data corresponding to these figures is tabulated below.
Figure imgf000055_0001
Figure imgf000055_0002
Figure imgf000055_0003
Figure imgf000056_0001
[00269] Figure 6 compares the efficacy of combinations of the disclosure with known/existing drug-Erlotinib, which is approved, and currently a market leader in lung cancer therapy. The comparison was done across clinically-measurable parameters of viability. The decrease in viability seen in HI 299, HCTl 16, and MDA-MB-231 with erlotinib is much less than 10%. In comparison to this response, the decrease seen in all three tumor profiles is 30% or greater with CWG89. The data corresponding for this figure is tabulated below.
Figure imgf000056_0002
EXAMPLES
[00270] The present disclosure is further elucidated by the following illustrative, limiting examples.
Figure imgf000056_0003
Comparative Analysis between mono (CW229) & COMBO ( Figures 22
Example 13
CWG89) on HCT116 human colon cancer cell line and 23
Comparative Analysis between mono (CW178) & COMBO ( Figures 24
Example 14
CWG89) on MDA-MB-231 human breast cancer cell line and 25
Comparative Analysis between mono (CW229) & COMBO ( Figures 26
Example 15
CWG89) on MDA-MB-231 human breast cancer cell line and 27
EXAMPLE 1: Effect of CW178 on H1299 human nine cancer cell line-PHASE 1 Study.
Experimental Protocol
[00271] The NCI-H1299 was procured from ATCC (American Type Culture Collection,
Manassas, VA).
[00272] NCI-H1299 (CRL-5803™) was cultured in BD Falcon (353109) tissue culture flask with vented cap T25 in RPMI 1640 (Invitrogen 22400-071) supplemented with 10% fetal bovine serum (Invitrogen 10437-010), IX MEM Sodium Pyruvate Solution (Invitrogen 11360- 070) and IX penicillin and streptomycin (Invitrogen 15140-122) in a humidified, 5% C02, 37 °C incubator.
[00273] Cell feeding (splitting) was timed such that the cells were in exponential growth phase at the time of the assay.
[00274] A dose response for CW178 was studied on HI 299 to determine the appropriate dose of compounds to test in Phase II. The compounds were tested in duplicate. The treatments were evaluated in triplicate.
[00275] CW178 was procured from Sigma-Aldrich Co. LLC, St. Louis, MO; Catalog #
PHR1084.
[00276] Compound stock solutions were prepared using aseptic techniques. The compounds remained in stock solution in soluble form with no visible precipitation observed. Due to the low solubility of CW178, a lOOmM stock solution was prepared fresh on the day of experiment using cell growth media.
[00277] Once prepared, compound was delivered in 50ul volume into each well of a 96- well tissue culture plate (Corning® Costar® 3596) in triplicate.
[00278] Upon addition of cells (4000 cells/well of HI 299 was used to maximize a dynamic range) into wells containing compound mixtures, the assay plate was covered and placed in a humidified, 5% C02, 37 °C incubator.
[00279] Four hours before the end of 24, 48, or 72 hours of assay incubation duration, 20 ul of tetrazolium compound (Promega CellTiter 96® AQueous One Solution) was added to each well and the plate returned to the humidified, 5% C02, 37 °C incubator for an additional four hours of incubation. Absorbance of each well was measured at 490 nm and 650 nm-reference after 2 or 4 hours of adding the reagent. Wells without cells (assay buffer alone) served as blank. Data used in analysis were taken from absorbance reading time of 2 or 4 hours. The standard deviation was calculated from the three values obtained from each of the replicate data point. No further statistical analysis was performed. Percent decrease in viability was calculated using the following formula: 100 x [Abs(untreated control) - Abs(experiment)]/[Abs(untreated control)]. Results
[00280] CW178 showed a progressively higher reduction in cell viability with increasing dosages, which reached greater than 65% reduction at 50 mM (Figure7). The data
corresponding to the figure is tabulated below.
Figure imgf000058_0001
EXAMPLE 2: Effect of CW178 on HCT116 human colon cancer cell line - Phase 1 Study. Experimental Protocol
[00281] HCT116 was procured from ATCC (American Type Culture Collection,
Manassas, VA).
[00282] HCT 116 (CCL-247™) were cultured in BD Falcon (353109) tissue culture flask with vented cap T25 in McCoy's 5 A Modified (Invitrogen 16600-082) supplemented with 10% fetal bovine serum and penicillin and streptomycin in a humidified, 5% C02, 37 °C incubator.
[00283] Cell feeding (splitting) was timed such that the cells were in exponential growth phase at the time of the assay.
[00284] A dose response for CW178 was studied on HCT116 to determine the appropriate dose of compounds to test in Phase II. The compounds were tested in dublicate. The treatments were evaluated in triplicate.
[00285] CW178 was procured from Sigma-Aldrich Co. LLC, St. Louis, MO; Catalog #
PHR1084.
[00286] Compound stock solutions were prepared using aseptic techniques. The compounds remained in stock solution in soluble form with no visible precipitation observed. Due to the low solubility of CW178, a 100 mM stock solution was prepared fresh on the day of experiment using cell growth media. [00287] Once prepared, compound was delivered in 50 ul volume into each well of a 96- well tissue culture plate (Corning® Costar® 3596) in triplicate.
[00288] Upon addition of cells (8000 cells/well of HCT116 was used to maximize a dynamic range) into wells containing compound mixtures, the assay plate was covered and placed in a humidified, 5% C02, 37 °C incubator.
[00289] Four hours before the end of 24, 48, or 72 hours of assay incubation duration, 20 ul of tetrazolium compound (Promega CellTiter 96® AQueous One Solution) was added to each well and the plate returned to the humidified, 5% C02, 37 °C incubator for an additional four hours of incubation. Absorbance of each well was measured at 490 nm and 650 nm-reference after 2 or 4 hours of adding the reagent. Wells without cells (assay buffer alone) served as blank. Data used in analysis were taken from absorbance reading time of 2 or 4 hours. The standard deviation was calculated from the three values obtained from each of the replicate data point. No further statistical analysis was performed. Percent decrease in viability was calculated using the following formula: 100 x [Abs(untreated control) - Abs(experiment)]/[Abs(untreated control)]. Results
[00290] CW178 showed a progressively higher reduction in Cell viability with increasing dosages and caused a decrease of more than 40% at 50mM (Figure 8). The data corresponding to the figure is tabulated below.
Figure imgf000059_0001
EXAMPLE 3: Effect of CW178 on MDA-MB-231 human breast cancer cell line - Phase 1
Study.
Experimental Protocol
[00291] MDA-MB-231 was procured from ATCC (American Type Culture Collection,
Manassas, VA).
[00292] MDA-MB-231 (HTB-26™) was cultured in BD Falcon (353109) tissue culture flask with vented cap T25 in McCoy's 5 A Modified (Invitrogen 16600-082) supplemented with 10% fetal bovine serum and penicillin and streptomycin in a humidified, 5% C02, 37 °C incubator.
[00293] Cell feeding (splitting) was timed such that the cells were in exponential growth phase at the time of the assay. [00294] A dose response for CW178 was studied on MDA-MB-231 to determine the appropriate dose of compounds to test in Phase II. The compounds were tested in dublicate. The treatments were evaluated in triplicate.
[00295] CW178 was procured from Sigma-Aldrich Co. LLC, St. Louis, MO; Catalog #
PHR1084.
[00296] Compound stock solutions were prepared using aseptic techniques. The compounds remained in stock solution in soluble form with no visible precipitation observed. Due to the low solubility of CW178, a 100 mM stock solution was prepared fresh on the day of experiment using cell growth media.
[00297] Once prepared, compound was delivered in 50 ul volume into each well of a 96- well tissue culture plate (Corning® Costar® 3596) in triplicate.
[00298] Upon addition of cells (8000 cells/well of MDA-MB-231 was used to maximize a dynamic range) into wells containing compound mixtures, the assay plate was covered and placed in a humidified, 5% C02, 37 °C incubator.
[00299] Four hours before the end of 24, 48, or 72 hours of assay incubation duration, 20 ul of tetrazolium compound (Promega CellTiter 96® AQueous One Solution) was added to each well and the plate returned to the humidified, 5% C02, 37 °C incubator for an additional four hours of incubation. Absorbance of each well was measured at 490 nm and 650 nm-reference after 2 or 4 hours of adding the reagent. Wells without cells (assay buffer alone) served as blank. Data used in analysis were taken from absorbance reading time of 2 or 4 hours. The standard deviation was calculated from the three values obtained from each of the replicate data point. No further statistical analysis was performed. Percent decrease in viability was calculated using the following formula: 100 x [Abs(untreated control) - Abs(experiment)]/[Abs(untreated control)]. Results
[00300] CW178 showed a progressively higher reduction in cell viability with increasing dosages and caused a decrease of -40% at 50 mM (Figure 9). The data corresponding to the figure is tabulated below.
Figure imgf000060_0001
EXAMPLE 4: Effect of CW229 on H1299 human lung cancer cell line - Phase 1 Study,
Experimental Protocol
[00301] The NCI-H1299 was procured from ATCC (American Type Culture Collection,
Manassas, VA).
[00302] NCI-H1299 (CRL-5803™) was cultured in BD Falcon (353109) tissue culture flask with vented cap T25 in RPMI 1640 (Invitrogen 22400-071) supplemented with 10% fetal bovine serum (Invitrogen 10437-010), IX MEM Sodium Pyruvate Solution (Invitrogen 11360- 070) and IX penicillin and streptomycin (Invitrogen 15140-122) in a humidified, 5% C02, 37 °C incubator.
[00303] Cell feeding (splitting) was timed such that the cells were in exponential growth phase at the time of the assay.
[00304] A dose response for CW229 was studied on HI 299 to determine the appropriate dose of compounds to test in Phase II. The compounds were tested in duplicate. The treatments were evaluated in triplicate.
[00305] C W229 was procured from Selleck Chemicals, Houston, TX; Catalog # S 1077.
[00306] Compound stock solutions were prepared using aseptic techniques. The compounds remained in stock solution in soluble form with no visible precipitation observed. CW229 stock solutions were prepared in DMSO, aliquoted and stored in -20 °C freezer until needed on the day of experiment.
[00307] Once prepared, compound was delivered in 50 ul volume into each well of a 96- well tissue culture plate (Corning® Costar® 3596) in triplicate.
[00308] Upon addition of cells (4000 cells/well of H1299 was used to maximize a dynamic range) into wells containing compound mixtures, the assay plate was covered and placed in a humidified, 5% C02, 37 °C incubator.
[00309] Four hours before the end of 24, 48, or 72 hours of assay incubation duration, 20 ul of tetrazolium compound (Promega CellTiter 96® AQueous One Solution) was added to each well and the plate returned to the humidified, 5% C02, 37 °C incubator for an additional four hours of incubation. Absorbance of each well was measured at 490 nm and 650 nm-reference after 2 or 4 hours of adding the reagent. Wells without cells (assay buffer alone) served as blank. Data used in analysis were taken from absorbance reading time of 2 or 4 hours. The standard deviation was calculated from the three values obtained from each of the replicate data point. No further statistical analysis was performed. Percent decrease in viability was calculated using the following formula: 100 x [Abs(untreated control) - Abs(experiment)]/[Abs(untreated control)]. Results
[00310] CW229 showed a progressively higher reduction in cell viability with increasing dosages and caused a decrease of -80% at 75 uM (Figure 10). The data corresponding to the figure is tabulated below.
Figure imgf000062_0001
EXAMPLE 5: Effect of CW229 on HCT116 human colon cancer cell line - Phase 1 Study. Experimental Protocol
[00311] HCT116 was procured from ATCC (American Type Culture Collection,
Manassas, VA).
[00312] HCT116 (CCL-247™) were cultured in BD Falcon (353109) tissue culture flask with vented cap T25 in McCoy's 5 A Modified (Invitrogen 16600-082) supplemented with 10%> fetal bovine serum and penicillin and streptomycin in a humidified, 5% C02, 37 °C incubator.
[00313] Cell feeding (splitting) was timed such that the cells were in exponential growth phase at the time of the assay.
[00314] A dose response for CW229 was studied on HCT116 to determine the appropriate dose of compounds to test in Phase II. The compounds were tested in duplicate. The treatments were evaluated in triplicate.
[00315] CW229 was procured from Selleck Chemicals, Houston, TX; Catalog # S1077.
[00316] Compound stock solutions were prepared using aseptic techniques. The compounds remained in stock solution in soluble form with no visible precipitation observed. CW229 stock solutions were prepared in DMSO, aliquoted and stored in -20 °C freezer until needed on the day of experiment.
[00317] Once prepared, compound was delivered in 50 ul volume into each well of a 96- well tissue culture plate (Corning® Costar® 3596) in triplicate.
[00318] Upon addition of cells (8000 cells/well of HCT116 was used to maximize a dynamic range) into wells containing compound mixtures, the assay plate was covered and placed in a humidified, 5% C02, 37 °C incubator.
[00319] Four hours before the end of 24, 48, or 72 hours of assay incubation duration, 20 ul of tetrazolium compound (Promega CellTiter 96® AQueous One Solution) was added to each well and the plate returned to the humidified, 5% C02, 37 °C incubator for an additional four hours of incubation. Absorbance of each well was measured at 490 nm and 650 nm-reference after 2 or 4 hours of adding the reagent. Wells without cells (assay buffer alone) served as blank. Data used in analysis were taken from absorbance reading time of 2 or 4 hours. The standard deviation was calculated from the three values obtained from each of the replicate data point. No further statistical analysis was performed. Percent decrease in viability was calculated using the following formula: 100 x [Abs(untreated control) - Abs(experiment)]/[Abs(untreated control)]. Results
[00320] CW229 showed a progressively greater reduction in cell viability with increasing dosages and caused a decrease of greater than 80% at 75 uM (Figure 11). The data
corresponding to the figure is tabulated below.
Figure imgf000063_0001
EXAMPLE 6: Effect of CW229 on MDA-MB-231 human breast cancer cell line - Phase 1
Study.
Experimental Protocol
[00321] MDA-MB-231 was procured from ATCC (American Type Culture Collection,
Manassas, VA).
[00322] MDA-MB-231 (HTB-26™) was cultured in BD Falcon (353109) tissue culture flask with vented cap T25 in McCoy's 5 A Modified (Invitrogen 16600-082) supplemented with 10% fetal bovine serum and penicillin and streptomycin in a humidified, 5% C02, 37 °C incubator.
[00323] Cell feeding (splitting) was timed such that the cells were in exponential growth phase at the time of the assay.
[00324] A dose response for CW229 was studied on MDA-MB-231 to determine the appropriate dose of compounds to test in Phase II. The compounds were tested in duplicate. The treatments were evaluated in triplicate.
[00325] C W229 was procured from Selleck Chemicals, Houston, TX; Catalog # S 1077.
[00326] Compound stock solutions were prepared using aseptic techniques. The compounds remained in stock solution in soluble form with no visible precipitation observed. CW229 stock solutions were prepared in DMSO, aliquoted and stored in -20 °C freezer until needed on the day of experiment. [00327] Once prepared, compound was delivered in 50 ul volume into each well of a 96- well tissue culture plate (Corning® Costar® 3596) in triplicate.
[00328] Upon addition of cells (8000 cells/well of MDA-MB-231 was used to maximize a dynamic range) into wells containing compound mixtures, the assay plate was covered and placed in a humidified, 5% C02, 37 °C incubator.
[00329] Four hours before the end of 24, 48, or 72 hours of assay incubation duration, 20 ul of tetrazolium compound (Promega CellTiter 96® AQueous One Solution) was added to each well and the plate returned to the humidified, 5% C02, 37 °C incubator for an additional four hours of incubation. Absorbance of each well was measured at 490 nm and 650 nm-reference after 2 or 4 hours of adding the reagent. Wells without cells (assay buffer alone) served as blank. Data used in analysis were taken from absorbance reading time of 2 or 4 hours. The standard deviation was calculated from the three values obtained from each of the replicate data point. No further statistical analysis was performed. Percent decrease in viability was calculated using the following formula: 100 x [Abs(untreated control) - Abs(experiment)]/[Abs(untreated control)]. Results
[00330] CW229 showed a progressively greater reduction in cell viability with increasing dosages and caused a decrease of greater than 50% at 75 uM (Figure 12). The data
corresponding to the figure is tabulated below.
Figure imgf000064_0001
EXAMPLE 7: Effect of CWG89 on H1299 human lung cancer cell line- Phase II Study,
Experimental Protocol
[00331] The NCI-H1299 was procured from ATCC and cultured as explained in examples
1 and 4 above.
[00332] Phase II evaluated the effects of combination of C Wl 78 and C W229 on cell viability against HI 299.
Treatment Groups
[00333] The cells were divided into three groups
Groupl: Control (Untreated)
Group2: Low dosage: A two drug combination was administered with a dosage composition of CW229 (SB202190) - 30 uM CW178 (Metformin)- 30 mM
Group3: High dosage: A two drug combination was administered with a dosage composition of CW229 (SB202190) - 45 uM
CW178 (Metformin) - 40 mM.
[00334] High and low compound dose chosen was based on results obtained from Phase I.
[00335] The efficacy of the two drug combination was compared to untreated control cells that received the equivalent volume of DMSO present in treated wells. Cells incubated with medium alone were also included.
Results
[00336] The two drug combination showed a significant effect with a 54% reduction cell viability at low dosage and a 71% reduction at high dosage (Figure 13). The data corresponding to the figure is tabulated below.
Figure imgf000065_0001
EXAMPLE 8: Effect of CWG89 on HCT116 human colon cancer cell line- Phase II Study. Experimental Protocol
[00337] The HCT116 was procured from ATCC and cultured as explained in examples 2 and 5 above.
[00338] Phase II evaluated the effects of combination of C Wl 78 and C W229 on cell viability against HCT116.
Treatment Groups
[00339] The cells were divided into three groups:
Groupl: Control (Untreated)
Group2: Low dosage: A two drug combination was administered with a dosage composition of CW229 (SB202190) - 30 uM
CW178 (Metformin) - 30 mM
Group3: High dosage: A two drug combination was administered with a dosage composition of CW229 (SB202190) - 45 uM
CW178 (Metformin) - 40 mM. [00340] High and low compound dose chosen was based on results obtained from Phase I.
[00341] The efficacy of the two drug combination was compared to untreated control cells that received the equivalent volume of DMSO present in treated wells. Cells incubated with medium alone were also included.
Results
[00342] The two drug combination showed a significant effect with a 32% reduction cell viability at low dosage and a 78% reduction at high dosage (Figure 14). The data corresponding to the figure is tabulated below.
Figure imgf000066_0001
EXAMPLE 9: Effect of CWG89 on MDA-MB-231 human breast cancer cell line- Phase II
Study.
Experimental Protocol
[00343] The MDA-MB-231 was procured from ATCC and cultured as explained in examples 3 and 6 above.
[00344] Phase II evaluated the effects of combination of C Wl 78 and C W229 on cell viability against MDA-MB-231.
Treatment Groups
[00345] The cells were divided into three groups:
Groupl: Control (Untreated)
Group2: Low dosage: A two drug combination was administered with a dosage composition of CW229 (SB202190) - 30 uM
CW178 (Metformin) - 30 mM
Group3: High Dosage: A two drug combination was administered with a dosage composition of CW229 (SB202190) - 45 uM
CW178 (Metformin) - 40 mM.
[00346] High and low compound dose chosen was based on results obtained from Phase I.
[00347] The efficacy of the two drug combination was compared to untreated control cells that received the equivalent volume of DMSO present in treated wells. Cells incubated with medium alone were also included.
Results
[00348] The two drug combination showed a significant effect with a 18% reduction cell viability at low dosage and a 32% reduction at high dosage (Figure 15). The data corresponding to the figure is tabulated below.
Figure imgf000067_0001
EXAMPLE 10: Comparative Analysis between CW178 and CWG89 treatment on the
H1299 human lung cancer cell line,
Experimental Protocol
Experiments were conducted as per the protocol given in Example 7.
Treatment Groups
[00349] The cells were divided into two groups:
Groupl: Control (Untreated)
Group2: CW178 (Metformin) - 30 mM
Group3: CW178 (Metformin) - 40 mM
Group4: A two drug combination was administered with a dosage composition of
CW178 (Metformin) - 40 mM
CW229 (SB202190) - 45 uM.
Results
[00350] The two drug combination showed a significant effect with a 71% reduction cell viability in NCI-H1299 cell line when compared to the mono therapy with CW178.
[00351] The results also showed a significant correlation to the predicted effect of the combination therapy for the data obtained from the Instant predictive technology (Figures 16 and 17). The data for the mentioned figures is tabulated below. Tabulation of Data on Figure 16
Percentage Change in Viability in Predictive (Virtual) System
CW178 -9.75
CWG89 -30.65
Tabulation of Data on Figure 17
Percentage Reduction in Viability in Cancer Cell Line
CW178-30mM -12
CW178-40mM -16
CWG89 -71
EXAMPLE 11: Comparative analysis between CW229 and CWG89 treatment on the
H1299 human lung cancer cell line,
Experimental Protocol
[00352] Experiments were conducted as per the protocol given in Example 7.
Treatment Groups
[00353] The cells were divided into two groups:
Groupl: Control (Untreated)
Group2: CW229 (SB202190) - 30 uM
Group3: CW229 (SB202190) - 45 uM
Group4: A two drug combination was administered with a dosage composition of
CW178 (Metformin) - 40 mM
CW229 (SB202190) - 45 uM.
Results
[00354] The two drug combination showed a significant effect with a 71% reduction cell viability in NCI-H1299 cell line when compared to the mono therapy with CW229.
[00355] The results also showed a significant correlation to the predicted effect of the combination therapy for the data obtained from the instant predictive technology (Figures 18 and 19). The data for the mentioned figures is as below.
Figure imgf000068_0001
Tabulation of Data of Figure 19
Percentage Reduction in Viability in Cancer Cell Line
CW229-30uM -20
CW229-45uM -41
CWG89 -71
[00356] Synergistic inhibitory effect is defined by a magnitude of inhibition of cell viability by two or three compounds that is greater than the sum of the magnitude of inhibition of each constituent compound. A synergistic effect of the combination CWG89 is seen, as illustrated in the table below, comparing the effect of individual drugs CW178 and CW229 with the combination CWG89 in the NCI-H1299 cell line. (Data corresponding to figures 17 and 19).
Figure imgf000069_0001
EXAMPLE 12: Comparative analysis between CW178 and CWG89 on the HCT116 human colon cancer cell line,
Experimental Protocol
[00357] Experiments were conducted as per the protocol given in Example 7.
Treatment Groups
[00358] The cells were divided into two groups:
Groupl: Control (Untreated)
Group2: CW178 (Metformin) - 30 mM
Group3: CW178 (Metformin) - 40 mM
Group4: A two drug combination was administered with a dosage composition of
CW178 (Metformin) - 40 mM
CW229 (SB202190) - 45 uM.
Results
[00359] The two drug combination showed a significant effect with a 78% reduction cell viability when compared to the mono therapy with CW178.
[00360] The results also showed a significant correlation to the predicted effect of the combination therapy for the data obtained from the Instant predictive technology (Figures 20 and 21). The data for the mentioned figures is tabulated below.
Figure imgf000070_0001
EXAMPLE 13: Comparative analysis between CW229 and CWG89 on the HCT116 human colon cancer cell line,
Experimental Protocol
[00361] Experiments were conducted as per the protocol given in Example 7.
Treatment Groups
[00362] The cells were divided into two groups:
Groupl: Control (Untreated)
Group2: CW229 (SB202190) - 30 uM
Group3: CW229 (SB202190) - 45 uM
Group4: A two drug combination was administered with a dosage composition of
CW178 (Metformin) - 40 mM
CW229 (SB202190) - 45 uM.
Results
[00363] The two drug combination showed a significant effect with a78% reduction cell viability when compared to the mono therapy with CW229.
[00364] The results also showed a significant correlation to the predicted effect of the combination therapy for the data obtained from the Instant predictive technology (Figures 22 and 23). The data for the mentioned figures is as below. Tabulation of Data on Figure 22
Percentage Change in Viability in Predictive (Virtual) System
CW229 -32.04
CWG89 -47.33
Tabulation of Data on Figure 23
Percentage Reduction in Viability in Cancer Cell Line
CW229-30uM -3
CW229-45uM -41
CWG89 -78
[00365] Synergistic inhibitory effect is defined by a magnitude of inhibition of cell viability by two or three compounds that is greater than the sum of the magnitude of inhibition of each constituent compound. A synergistic effect of the combination CWG89 is seen, as illustrated in the table below, comparing the effect of individual drugs CW178 and CW229 with the combination CWG89 in the HCTl 16 cell line. (Data corresponding to figures 21 and 23).
Figure imgf000071_0001
EXAMPLE 14: Comparative analysis between CW178 and CWG89 on the MDA-MB-231 human colon cancer cell line,
Experimental Protocol
[00366] Experiments were conducted as per the protocol given in Example 7.
Treatment Groups
[00367] The cells were divided into two groups:
Groupl: Control (Untreated)
Group2: CW178 (Metformin) - 30 mM
Group3: CW178 (Metformin) - 40 mM
Group4: A two drug combination was administered with a dosage composition of
CW178 (Metformin) - 40 mM
CW229 (SB202190) - 45 uM. Results
[00368] The two drug combination showed a significant effect with a 32% reduction cell viability when compared to the mono therapy with CW178.
[00369] The results also showed a significant correlation to the predicted effect of the combination therapy for the data obtained from the Instant predictive technology (Figures 24 and 25). The data for the mentioned figures is tabulated below.
Figure imgf000072_0001
EXAMPLE 15: Comparative analysis between CW229 and CWG89 on the MDA-MB-231 human colon cancer cell line,
Experimental Protocol
[00370] Experiments were conducted as per the protocol given in Example 7.
Treatment Groups
[00371] The cells were divided into two groups:
Groupl: Control (Untreated)
Group2: CW229 (SB202190) - 30 uM
Group3: CW229 (SB202190) - 45 uM
Group4: A two drug combination was administered with a dosage composition of
CW178 (Metformin) - 40 mM
CW229 (SB202190) - 45 uM.
Results
[00372] The two drug combination showed a significant effect with a 32% reduction cell viability when compared to the mono therapy with CW229.
[00373] The results also showed a significant correlation to the predicted effect of the combination therapy for the data obtained from the Instant predictive technology (Fig and 27). The data for the mentioned figures is tabulated below.
Figure imgf000073_0001
[00374] Synergistic inhibitory effect is defined by a magnitude of inhibition of cell viability by two or three compounds that is greater than the sum of the magnitude of inhibition of each constituent compound. A synergistic effect of the combination CWG89 is seen, as illustrated in the table below, comparing the effect of individual drugs CW178 and CW229 with the combination CWG89 in the MDA-MB-231 cell line. (Data corresponding to figures 25 and 27).
Figure imgf000073_0002

Claims

WHAT IS CLAIMED IS:
1. A composition comprising:
a) i) an AMPK activator; and
ii) an inhibitor of P38-MAPK activity; and
b) a pharmaceutically-acceptable excipient,
wherein the composition is a unit dosage form.
2. The composition of claim 1, wherein the AMPK activator is a compound of Formula (I):
R2 R3 R4
Figure imgf000074_0001
(I), wherein each of R1, R2, R3, R4, and R5 is independently H, OH, SH, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, or
alkylheterocyclyl, wherein each alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, and alkylheterocyclyl group is independently unsubstituted or substituted, or any two of R1, R2, R3, R4, and R5 form a ring together with the atoms to which they are bound, wherein the ring is unsubstituted or substituted;
each of X and Y is independently O, S, C(R6)(R7), N+(R6)(R7), or N(R6); and each of R6 and R7 is independently H, OH, SH, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, or alkylheterocyclyl, wherein each alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, and alkylheterocyclyl group is independently unsubstituted or substituted, or R6 and R7 form a ring with the atoms to which they are bound, wherein the ring is unsubstituted or substituted,
or a pharmaceutically-acceptable salt thereof.
3. The composition of claim 2, wherein:
each of R1, R2, R3, R4, and R5 is independently H, alkyl, alkenyl, aryl, arylalkyl, or alkylaryl, wherein each alkyl, alkenyl, aryl, arylalkyl, and alkylaryl group is independently unsubstituted or substituted;
each of X and Y is independently N(R6); and
each R6 is independently H, alkyl, alkenyl, aryl, arylalkyl, or alkylaryl, wherein each alkyl, alkenyl, aryl, arylalkyl, and alkylaryl, group is independently unsubstituted or substituted.
4. The composition of claim 3, wherein:
each of R1, R2, R3, R4, and R5 is independently H, alkyl, or arylalkyl;
each of X and Y is independently N(R6); and
each R6 is independently H or alkyl.
5. The composition of claim 4, wherein:
each of R1 , R2 and R3 is H;
each of R4 and R5 is alkyl;
each of X and Y is N(R6); and
each R6 is H.
6. The composition of claim 4, wherein:
each of R1, R2, R3, and R4 is H;
R5 is arylalkyl;
each of X and Y is N(R6); and
each R6 is H.
7. The composition of claim 1, wherein the inhibitor of P38-MAPK activity is a compound of Formula (VI):
O
Het Aryl (VI), wherein:
Het is a heterocycle that is unsubstituted or substituted; and
Aryl is an aryl group that is unsubstituted or substituted, or a pharmaceutically-acceptable salt thereof.
8. The composition of claim 7, wherein the compound of Formula (VI) is a compound of Formula (VII):
Figure imgf000076_0001
(VII), wherein:
R18 is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, or alkylheterocyclyl, wherein the alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, and alkylheterocyclyl group is unsubstituted or substituted;
each of R 19 , R 20 , and R 21 is independently H, OH, SH, halogen, amino, mono- substituted amino, di-substituted amino, alkyl, aryl, heterocyclyl, an ester group, an alkoxy group, a thioether group, an amido group, or a carbamate group;
p is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and
q is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
9. The composition of claim 8, wherein the compound of Formula (VI) is a compound of Formula (VIII):
Figure imgf000076_0002
(VIII), wherein:
R18 is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, or alkylheterocyclyl, wherein the alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, and alkylheterocyclyl group is unsubstituted or substituted; and
each of R19 and R20 is independently H, OH, SH, halogen, amino, mono- substituted amino, di-substituted amino, alkyl, aryl, heterocyclyl, an ester group, an alkoxy group, a thioether group, an amido group, or a carbamate group.
10. The composition of claim 1, wherein the AMPK activator is phenformin.
11. The composition of claim 1 , wherein the AMPK activator is metformin.
12. The composition of claim 1, wherein the inhibitor of P38-MAPK activity is
SB681323.
13. The composition of claim 11, wherein the inhibitor of P38-MAPK activity is
SB681323.
14. The composition of claim 1 , wherein each of the AMPK activator and the inhibitor of P38-MAPK activity is independently present in an amount from about 10% to about 50% of a maximum tolerated dose.
15. The composition of claim 1, wherein each of the AMPK activator and the inhibitor of P38-MAPK activity is independently present in an amount from about 1 mg to about 2000 mg.
16. The composition of claim 1, wherein the AMPK activator is present in an amount from about 100 mg/kg to about 2000 mg/kg of subject body mass.
17. The composition of claim 1, wherein the inhibitor of P38-MAPK activity is present in an amount from about 3 mg/kg to about 100 mg/kg of subject body mass.
18. The composition of claim 1, wherein the unit dosage form provides a delayed release of at least one of the AMPK activator and the inhibitor of P38-MAPK activity.
19. The composition of claim 1, wherein the unit dosage form is formulated for oral administration.
20. The composition of claim 19, wherein the unit dosage form is formulated for delayed release of the AMPK activator.
21. The composition of claim 20, wherein the AMPK activator is metformin.
22. The composition of claim 19, wherein the unit dosage form is formulated for delayed release of the inhibitor of P38-MAPK activity.
23. The composition of claim 22, wherein the inhibitor of P38-MAPK activity is
SB681323.
24. The composition of claim 1, wherein the unit dosage form is a tablet comprising: a) a core containing one of: the AMPK activator and the inhibitor of P38-MAPK activity; and
b) an outer layer containing one of: the AMPK activator and the inhibitor of P38- MAPK activity.
25. The composition of claim 24, wherein the core provides a delayed release.
26. The composition of claim 24, wherein each of the AMPK activator and the inhibitor of P38-MAPK activity is independently present in an amount from about 10% to about 50% of a maximum tolerated dose.
27. A kit comprising:
a) i) an AMPK activator; and
ii) an inhibitor of P38-MAPK activity; and
b) written instructions on use of the kit.
28. The kit of claim 27, wherein the written instructions explain use of the kit in a therapy for a cancer.
29. The kit of claim 27, wherein the AMPK activator is a compound of Formula (I):
Figure imgf000079_0001
(I), wherein
each of R1, R2, R3, R4, and R5 is independently H, OH, SH, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, or
alkylheterocyclyl, wherein each alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, and alkylheterocyclyl group is independently unsubstituted or substituted, or any two of R1, R2, R3, R4, and R5 form a ring together with the atoms to which they are bound, wherein the ring is unsubstituted or substituted;
each of X and Y is independently O, S, C(R6)(R7), N+(R6)(R7), or N(R6); and each of R6 and R7 is independently H, OH, SH, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, or alkylheterocyclyl, wherein each alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, and alkylheterocyclyl group is independently unsubstituted or substituted, or R6 and R7 form a ring with the atoms to which they are bound, wherein the ring is
unsubstituted or substituted,
or a pharmaceutically-acceptable salt thereof.
The kit of claim 29, wherein:
each of R1, R2, R3, R4, and R5 is independently H, alkyl, alkenyl, aryl, arylalkyl, or alkylaryl, wherein each alkyl, alkenyl, aryl, arylalkyl, and alkylaryl group is independently unsubstituted or substituted;
each of X and Y is independently N(R6); and
each R6 is independently H, alkyl, alkenyl, aryl, arylalkyl, or alkylaryl, wherein each alkyl, alkenyl, aryl, arylalkyl, and alkylaryl, group is independently unsubstituted or substituted.
31. The kit of claim 30, wherein:
each of R1, R2, R3, R4, and R5 is independently H, alkyl, or arylalkyl;
each of X and Y is independently N(R6); and
each R6 is independently H or alkyl.
32. The kit of claim 31 , wherein:
each of R1, R2 and R3 is H;
each of R4 and R5 is alkyl;
each of X and Y is N(R6); and
each R6 is H.
33. The kit of claim 31 , wherein:
each of R1, R2, R3, and R4 is H;
R5 is arylalkyl;
each of X and Y is N(R6); and
each R6 is H.
The kit of claim 27, wherein the inhibitor of P38-MAPK activity is a compound of
Figure imgf000080_0001
Het (VI), wherein:
Het is a heterocycle that is unsubstituted or substituted; and
Aryl is an aryl group that is unsubstituted or substituted,
or a pharmaceutically-acceptable salt thereof.
35. The kit of claim 34, wherein the compound of Formula (VI) is a compound of Formula
(VII):
Figure imgf000080_0002
R 18 (VII), wherein:
R18 is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, or alkylheterocyclyl, wherein the alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, and alkylheterocyclyl group is unsubstituted or substituted;
each of R 19 , R 20 , and R 21 is independently H, OH, SH, halogen, amino, mono- substituted amino, di-substituted amino, alkyl, aryl, heterocyclyl, an ester group, an alkoxy group, a thioether group, an amido group, or a carbamate group;
p is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and
q is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
The kit of claim 35, wherein the compound of Formula (VI) is a compound of Formula
Figure imgf000081_0001
R18 is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, or alkylheterocyclyl, wherein the alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, and alkylheterocyclyl group is unsubstituted or substituted; and
each of R19 and R20 is independently H, OH, SH, halogen, amino, mono- substituted amino, di-substituted amino, alkyl, aryl, heterocyclyl, an ester group, an alkoxy group, a thioether group, an amido group, or a carbamate group.
37. The kit of claim 27, wherein the AMPK activator is phenformin.
38. The kit of claim 27, wherein the AMPK activator is metformin.
39. The kit of claim 27, wherein the inhibitor of P38-MAPK activity is SB681323.
40. The kit of claim 38, wherein the inhibitor of P38-MAPK activity is SB681323.
41. The kit of claim 27, wherein the kit comprises a unit dosage form containing one of i) and ii).
42. The kit of claim 27, wherein the kit comprises a unit dosage form containing two of i) and ii).
43. The kit of claim 42, wherein the AMPK activator is metformin and the inhibitor of P38-MAPK activity is SB681323.
44. The kit of claim 42, wherein the written instructions explain use of the kit in a therapy for a cancer.
45. The kit of claim 42, wherein each of the AMPK activator and the inhibitor of P38- MAPK activity is independently present in the unit dosage form in an amount from about 10% to about 50% of a maximum tolerated dose.
46. The kit of claim 42, wherein each of the AMPK activator and the inhibitor of P38- MAPK activity is independently present in the unit dosage form in an amount from about 1 mg to about 2000 mg.
47. The kit of claim 42, wherein the AMPK activator is present in the unit dosage form in an amount from about 100 mg/kg to about 2000 mg/kg of subject body mass.
48. The kit of claim 42, wherein the inhibitor of P38-MAPK activity is present in the unit dosage form in an amount from about 3 mg/kg to about 100 mg/kg of subject body mass.
49. The kit of claim 42 wherein the unit dosage form provides a delayed release of at least one of the AMPK activator and the inhibitor of P38-MAPK activity.
50. The kit of claim 42, wherein the unit dosage form is formulated for oral
administration.
51. A method for treating a cancer in a subject in need or want of relief thereof, the method comprising administering to the subject:
i) a therapeutically-effective amount of an AMPK activator; and
ii) a therapeutically-effective amount of an inhibitor of P38-MAPK activity. The method of laim 51, wherein the AMPK activator is a compound of Formula (I)
Figure imgf000083_0001
(I), wherein
each of R1, R2, R3, R4, and R5 is independently H, OH, SH, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, or
alkylheterocyclyl, wherein each alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, and alkylheterocyclyl group is independently unsubstituted or substituted, or any two of R1, R2, R3, R4, and R5 form a ring together with the atoms to which they are bound, wherein the ring is unsubstituted or substituted;
each of X and Y is independently O, S, C(R6)(R7), N+(R6)(R7), or N(R6); and each of R6 and R7 is independently H, OH, SH, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, or alkylheterocyclyl, wherein each alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, and alkylheterocyclyl group is independently unsubstituted or substituted, or R6 and R7 form a ring with the atoms to which they are bound, wherein the ring is
unsubstituted or substituted,
rmaceutically-acceptable salt thereof.
The method of claim 52, wherein:
each of R1, R2, R3, R4, and R5 is independently H, alkyl, alkenyl, aryl, arylalkyl, or alkylaryl, wherein each alkyl, alkenyl, aryl, arylalkyl, and alkylaryl group is independently unsubstituted or substituted;
each of X and Y is independently N(R6); and
each R6 is independently H, alkyl, alkenyl, aryl, arylalkyl, or alkylaryl, wherein each alkyl, alkenyl, aryl, arylalkyl, and alkylaryl, group is independently unsubstituted or substituted.
The method of claim 53, wherein:
each of R1, R2, R3, R4, and R5 is independently H, alkyl, or arylalkyl; each of X and Y is independently N(R6); and
each R6 is independently H or alkyl.
55. The method of claim 54, wherein:
each of R1, R2 and R3 is H;
each of R4 and R5 is alkyl;
each of X and Y is N(R6); and
each R6 is H.
56. The method of claim 54, wherein:
each of R1, R2, R3, and R4 is H;
R5 is arylalkyl;
each of X and Y is N(R6); and
each R6 is H.
The method of claim 51, wherein the inhibitor of P38-MAPK activity is a compound of
Figure imgf000084_0001
Het (VI), wherein:
Het is a heterocycle that is unsubstituted or substituted; and
Aryl is an aryl group that is unsubstituted or substituted,
or a pharmaceutically-acceptable salt thereof.
The method of claim 57, wherein the compound of Formula (VI) is a compound of
Figure imgf000084_0002
R 18 (VII), wherein: R18 is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, or alkylheterocyclyl, wherein the alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, and alkylheterocyclyl group is unsubstituted or substituted;
each of R 19 , R 20 , and R 21 is independently H, OH, SH, halogen, amino, mono- substituted amino, di-substituted amino, alkyl, aryl, heterocyclyl, an ester group, an alkoxy group, a thioether group, an amido group, or a carbamate group;
p is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and
q is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
59. The method of claim 58, wherein the compound of Formula (VI) is a compound of Formula (VIII):
Figure imgf000085_0001
R18 is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, or alkylheterocyclyl, wherein the alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocyclylalkyl, and alkylheterocyclyl group is unsubstituted or substituted; and
each of R19 and R20 is independently H, OH, SH, halogen, amino, mono- substituted amino, di-substituted amino, alkyl, aryl, heterocyclyl, an ester group, an alkoxy group, a thioether group, an amido group, or a carbamate group.
60. The method of claim 51 , wherein the AMPK activator is phenformin.
61. The method of claim 51 , wherein the AMPK activator is metformin.
62. The method of claim 51, wherein the inhibitor of P38-MAPK activity is SB681323.
63. The method of claim 61 , wherein the inhibitor of P38-MAPK activity is SB681323.
64. The method of claim 51 , wherein the therapeutically-effective amount of each of the AMPK activator and the inhibitor of P38-MAPK activity is independently from about 10% to about 50% of a maximum tolerated dose.
65. The method of claim 51 , wherein the AMPK activator and the inhibitor of P38- MAPK activity are administered simultaneously.
66. The method of claim 51 , wherein the AMPK activator and the inhibitor of P38- MAPK activity are administered sequentially.
67. The method of claim 51 , wherein at least one of the AMPK activator and the inhibitor of P38-MAPK activity is administered by a delayed release mechanism.
68. The method of claim 67, wherein the delayed release mechanism delays release of at least one of the AMPK activator and the inhibitor of P38-MAPK activity for about 8 hours.
69. The method of claim 67, wherein the delayed release mechanism delays release of at least one of the AMPK activator and the inhibitor of P38-MAPK activity for about 12 hours.
70. The method of claim 67, wherein the delayed release mechanism delays release of at least one of the AMPK activator and the inhibitor of P38-MAPK activity for about 16 hours.
71. The method of claim 51 , wherein the subject has an AU o-inf) of one of the AMPK activator and the inhibitor of P38-MAPK activity of not less than 250 ng»hr/mL.
72. The method of claim 51 , wherein the subject has a plasma concentration of one of the AMPK activator and the inhibitor of P38-MAPK activity of not less than 25 ng/mL.
73. The method of claim 51 , wherein at least one of the AMPK activator and the inhibitor of P38-MAPK activity is administered orally.
74. The method of claim 51 , wherein the cancer is a colorectal cancer.
75. The method of claim 51 , wherein the cancer is lung cancer.
76. The method of claim 51 , wherein the cancer is glioblastoma.
77. The method of claim 51 , wherein the cancer is associated with a mutation in KRAS.
78. The method of claim 77, wherein the cancer is associated with a mutation in BRAF.
79. The method of claim 51 , wherein the cancer is associated with a mutation in BRAF.
80. The method of claim 51 , wherein the therapeutically-effective amount of the AMPK activator and the inhibitor of P38-MAPK activity is independently from about 1 mg to about 2000 mg.
81. The method of claim 51 , wherein:
a) the therapeutically-effective amount of the AMPK activator is from about 100 mg/kg to about 2000 mg/kg of subject body mass; and
b) the therapeutically-effective amount of the inhibitor of P38-MAPK activity is from about 3 mg/kg to about 100 mg/kg.
82. The method of claim 51 , wherein at least one of the AMPK activator and the inhibitor of P38-MAPK activity is administered orally.
83. The method of claim 51, comprising administering to the subject a unit dosage form containing one of i) and ii).
84. The method of claim 51, comprising administering to the subject a unit dosage form containing two of i) and ii).
85. The method of claim 84, wherein the unit dosage form is a tablet comprising:
a) a core containing one of: the AMPK activator and the inhibitor of P38-MAPK activity; and
b) an outer layer containing one of: the AMPK activator and the inhibitor of P38- MAPK activity. The method of claim 85, wherein the core provides a delayed release.
PCT/US2012/067956 2011-12-05 2012-12-05 Compositions, process of preparation of said compositions and method of treating cancer WO2013086002A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN4232/CHE/2011 2011-12-05
IN4232CH2011 2011-12-05

Publications (1)

Publication Number Publication Date
WO2013086002A1 true WO2013086002A1 (en) 2013-06-13

Family

ID=48574827

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2012/067956 WO2013086002A1 (en) 2011-12-05 2012-12-05 Compositions, process of preparation of said compositions and method of treating cancer

Country Status (1)

Country Link
WO (1) WO2013086002A1 (en)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9519275B2 (en) 2011-09-16 2016-12-13 Isuzu Motors Limited Actuator control method and actuator control device
JP2017538677A (en) * 2014-11-05 2017-12-28 フレクサス・バイオサイエンシーズ・インコーポレイテッドＦｌｅｘｕｓ Ｂｉｏｓｃｉｅｎｃｅｓ， Ｉｎｃ． Immunomodulator
US10342786B2 (en) 2017-10-05 2019-07-09 Fulcrum Therapeutics, Inc. P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD
CN110760582A (en) * 2019-07-10 2020-02-07 中山大学 Application of metformin in treatment of KRAS mutant colorectal cancer
WO2020215034A1 (en) * 2019-04-19 2020-10-22 The Regents Of The University Of California An ampk/caspase-6 axis controls liver damage in nonalcoholic steatohepatitis
US11291659B2 (en) 2017-10-05 2022-04-05 Fulcrum Therapeutics, Inc. P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030078274A1 (en) * 1999-07-02 2003-04-24 Lipton Stuart A. Method of reducing neuronal injury or apoptosis
WO2008110491A2 (en) * 2007-03-09 2008-09-18 University Of Basel Chemotherapy of neoplastic diseases using combinations of rapamycin and compounds modulating mtor pathway alone or in combination with heat
WO2008150899A1 (en) * 2007-05-29 2008-12-11 Emory University Combination therapies for treatment of cancer and inflammatory diseases
US20090098536A1 (en) * 2007-10-12 2009-04-16 C-A-I-R- Biosciences Gmbh Method for subgroup analysis in subjects having or being suspected of having inflammatory disease, use of anti-p38MAPK antibodies, kits and their use
WO2010103040A1 (en) * 2009-03-10 2010-09-16 INSERM (Institut National de la Santé et de la Recherche Médicale) 5'-adenosine monophosphate-activated protein kinase (ampk) activators for treating pulmonary hypertension
WO2011031474A2 (en) * 2009-08-25 2011-03-17 President And Fellows Of Harvard College Use of metformin in cancer treatment and prevention
WO2011044072A1 (en) * 2009-10-05 2011-04-14 Novartis Ag Combination of raf-265 and an activator of ampk for use in the treatment of a proliferative disease
US20110281829A1 (en) * 2010-04-28 2011-11-17 Ipintl, Llc Novel composition

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030078274A1 (en) * 1999-07-02 2003-04-24 Lipton Stuart A. Method of reducing neuronal injury or apoptosis
WO2008110491A2 (en) * 2007-03-09 2008-09-18 University Of Basel Chemotherapy of neoplastic diseases using combinations of rapamycin and compounds modulating mtor pathway alone or in combination with heat
WO2008150899A1 (en) * 2007-05-29 2008-12-11 Emory University Combination therapies for treatment of cancer and inflammatory diseases
US20090098536A1 (en) * 2007-10-12 2009-04-16 C-A-I-R- Biosciences Gmbh Method for subgroup analysis in subjects having or being suspected of having inflammatory disease, use of anti-p38MAPK antibodies, kits and their use
WO2010103040A1 (en) * 2009-03-10 2010-09-16 INSERM (Institut National de la Santé et de la Recherche Médicale) 5'-adenosine monophosphate-activated protein kinase (ampk) activators for treating pulmonary hypertension
WO2011031474A2 (en) * 2009-08-25 2011-03-17 President And Fellows Of Harvard College Use of metformin in cancer treatment and prevention
WO2011044072A1 (en) * 2009-10-05 2011-04-14 Novartis Ag Combination of raf-265 and an activator of ampk for use in the treatment of a proliferative disease
US20110281829A1 (en) * 2010-04-28 2011-11-17 Ipintl, Llc Novel composition

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SAROV-BLAT L. ET AL.: "Inhibition of p38 Mitogen-Activated Protein Kinase Reduces Inflammation After Coronary Vascular Injury in Humans", ARTERIOSCLER. THROMB. VASC. BIOL., vol. 30, 2010, pages 2256 - 2263, XP055072158 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9519275B2 (en) 2011-09-16 2016-12-13 Isuzu Motors Limited Actuator control method and actuator control device
JP2017538677A (en) * 2014-11-05 2017-12-28 フレクサス・バイオサイエンシーズ・インコーポレイテッドＦｌｅｘｕｓ Ｂｉｏｓｃｉｅｎｃｅｓ， Ｉｎｃ． Immunomodulator
EP3215142A4 (en) * 2014-11-05 2018-09-05 Flexus Biosciences, Inc. Immunoregulatory agents
US10206893B2 (en) 2014-11-05 2019-02-19 Flexus Biosciences, Inc. Immunoregulatory agents
US10342786B2 (en) 2017-10-05 2019-07-09 Fulcrum Therapeutics, Inc. P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD
US10537560B2 (en) 2017-10-05 2020-01-21 Fulcrum Therapeutics. Inc. P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD
US11291659B2 (en) 2017-10-05 2022-04-05 Fulcrum Therapeutics, Inc. P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD
US11479770B2 (en) 2017-10-05 2022-10-25 Fulcrum Therapeutics, Inc. Use of p38 inhibitors to reduce expression of DUX4
WO2020215034A1 (en) * 2019-04-19 2020-10-22 The Regents Of The University Of California An ampk/caspase-6 axis controls liver damage in nonalcoholic steatohepatitis
CN110760582A (en) * 2019-07-10 2020-02-07 中山大学 Application of metformin in treatment of KRAS mutant colorectal cancer
WO2021004372A1 (en) * 2019-07-10 2021-01-14 中山大学 Application of metformin in treatment of kras mutant colorectal cancer

Similar Documents

Publication Publication Date Title
US9532984B2 (en) Therapeutic combination for cancer treatment
EP3019166B1 (en) A pharmaceutical combination for the treatment of melanoma
WO2013086002A1 (en) Compositions, process of preparation of said compositions and method of treating cancer
US10350213B2 (en) Methods for treating cancer using apilimod
US20180078561A1 (en) Active metabolites of apilimod and uses thereof
US10098880B2 (en) Combination of nelfinavir, metformin and rosuvastatin for treating cancer caused by aberrations in PTEN/TP53
US10765682B2 (en) Apilimod for use in the treatment of melanoma
US20020156023A1 (en) Lometrexol combination therapy
TW201628622A (en) TLR inhibitor and BRUTON'S tyrosine kinase inhibitor combinations
JP2023109899A (en) Combinations comprising at least one spliceosome modulator and at least one inhibitor selected from bcl2 inhibitors, bcl2/bclxl inhibitors and bclxl inhibitors and methods of use
WO2013066483A1 (en) Synergistic combinations of pi3k- and mek-inhibitors
US20120308562A1 (en) Methods of treating mesothelioma with a pi3k inhibitor compound
US20220362209A1 (en) Methods and compositions for treating chemotherapy-induced diarrhea
US20120059005A1 (en) Combination of (a) a phosphoinositide 3-kinase inhibitor and (b) an antidiabetic compound for use in the treatment of proliferative diseases
US20220241294A1 (en) Bisfluoroalkyl-1,4-benzodiazepinone compounds for treating notch-activated breast cancer
US20140127295A1 (en) Compositions, process of preparation of said compositions and method of treating inflammatory diseases
CN113329749A (en) Combination therapy for the treatment of uveal melanoma
CA3218585A1 (en) Composition for treating autoimmune, alloimmune, inflammatory, and mitochondrial conditions, and uses thereof
US20220409582A1 (en) Combination therapies comprising panobinostat for the treatment of cholangiocarcinoma
CN114728003A (en) Therapeutic combinations of acatinib and caspasertinib for the treatment of B-cell malignancies
CN113453671A (en) Combination therapy of a Raf inhibitor and a CDK4/6 inhibitor for the treatment of cancer
EP4168027A1 (en) Methods and compositions for treating chemotherapy-induced diarrhea
WO2015068142A2 (en) Compositions, process of preparation of said compositions, uses and method of management of myeloproliferative disorder
RU2784869C1 (en) Chiauranib for treating small cell lung cancer
KR20110043531A (en) Antitumor agent, kit and method of treating cancer

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 12855413

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 12855413

Country of ref document: EP

Kind code of ref document: A1