TREATMENT OF DISEASES BY EPIGENETIC REGULATION
The present disclosure provides non-naturally occurring polyphenol compounds that inhibit the bromodomain and extra terminal domain (BET) proteins. The disclosed compositions and methods can be used for treatment and prevention of cancer as well as sepsis, including NUT midline carcinoma, Burkitt's Lymphoma, Acute Myelogenous Leukemia, and Multiple Myeloma.
1 . A method for inhibiting BET proteins in a mammal comprising administering a therapeutically effective amount of a compound of Formula I or a tautomer, stereoisomer, pharmaceutically acceptable salt, or hydrate thereof:
wherein:
R 1 , R 2 , R 3 , R 4 , R 6 , and R 8 , are each independently selected from (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, aryl, heteroaryl, alkoxy, aryloxy, arylalkyl, amino, carbonyl, benzyl, phenyl, thioketone, hydrogen, hydroxyl, hydroxyalkyl, aminoalkyl, amides, carbamates, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, heterocyclyl, haloalkyl, sulfonic acid [—SO 3 H], phosphate, sulfonate, O-glucoronidate [the glucoronic (AKA glucuronic) acid conjugates], dicarboxylic acid, ketone, nitro, sulfide, sulfinyl, sulfonyl, sulfonamide and #STR55#, #STR66#, #STR77#, #STR88#, #STR99#, #STR100#,
R 7 is selected from alkoxy, hydroxyl, hydroxyalkyl, ether, and ester, or
two adjacent substituents selected from R 1 , R 2 , R 3 , R 6 , R 7 , and R 8 , are connected in a 5 or 6-membered ring to form a bicyclic aryl or bicyclic heteroaryl when W 1 is N;
each W and/or W 1 is independently selected from C and N, wherein if W and/or W 1 is N, then p is 0 and if W and/or W 1 is C, then p is 1;
at least one W and/or W 1 is N;
wherein
R 15 and R 16 are substituents independently selected from the group consisting of (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, aryl, heteroaryl, alkoxy, aryloxy, benzyl, phenyl, carbonyl, hydrogen, hydroxyl [OH], acetyl, hydroxyalkyl, aminoalkyl, amides, carbamates, halogen, CF 3 , CCl 3 , sulfonic acid [—SO 3 H], phosphate, or a derivative thereof, wherein said derivative is optionally substituted and optionally branched, and may have one or more of the C atoms replaced by S, N or O.
2 . The method of claim 1 , wherein the therapeutically effective amount of the compound of Formula I is administered with a pharmaceutically acceptable carrier in a pharmaceutically acceptable composition.
3 . The method of claim 1 , wherein the therapeutically effective amount of the compound of Formula I is sufficient to establish a concentration ranging from about 0.001 μM to about 100 μM in the mammal.
4 . The method of claim 3 , wherein the concentration ranges from about 1 μM to about 20 μM.
5 . The method of claim 1 , wherein the compound of Formula I is selected from:
2-(4-Hydroxy-phenyl)-pyrano[2,3-b]pyridin-4-one
2-(4-Hydroxy-phenyl)-pyrano[3,2-b]pyridin-4-one
2-(4-Hydroxyphenyl)-pyrano[2,3-c]pyridin-4-one
2-(3-Fluoro-4-hydroxyphenyl)pyrano[2,3-b]pyridine-4-one
2-(4-Hydroxy-3-methylphenyl)-4H-pyrano[2,3-b]pyridine-4-one
2-(4-Hydroxyphenyl)-4H-pyrano[3,2-c]pyridin-4-one
2-(3-Chloro-4-hydroxyphenyl)-4H-pyrano[2,3-b]pyridine-4-one
2-(3-Bromo-4-hydroxyphenyl)-4H-pyrano[2,3-b]pyridin-4-one
2-(4-Hydroxy-3-methoxyphenyl)-4H-pyrano[2,3-b]pyridine-4-one
2-(4-Methoxyphenyl)-4H-pyrano[2,3-b]pyridine-4-one
2-(4-(2-Hydroxyethoxy)phenyl)-4H-pyrano[2,3-b]pyridine-4-one
4-(4-Oxo-4H-pyrano[2,3-b]pyridine-2-yl)phenyl acetate
2-(4-Hydroxy-3-(hydroxymethyl)phenyl)-4H-pyrano[2,3]-b]pyridine-4-one
and stereoisomers, tautomers, pharmaceutically acceptable salts, and hydrates thereof.
6 . The method of claim 5 , wherein the therapeutically effective amount of the compound is administered with a pharmaceutically acceptable carrier in a pharmaceutically acceptable composition.
7 . The method according to claim 1 , wherein the method comprises treating a disease or disorder that is sensitive to a BET inhibitor.
8 . The method of claim 1 , wherein the disease or disorder is a cancer.
9 . The method of claim 8 , wherein the cancer is selected from the group consisting of cancers that exhibit c-myc overexpression, cancers that overexpress n-myc, cancers that that rely on the recruitment of p-TEFb to regulate activated oncogenes, Burkitt's lymphoma, acute myelogenous leukemia, multiple myeloma, aggressive human medulloblastoma, hematological, epithelial including lung, breast and colon carcinomas, midline carcinomas, and mesenchymal, hepatic, renal and neurological tumors.
10 . The method of claim 8 , wherein, the compound induces apoptosis in cancer cells by decreasing expression of the anti-apoptosis gene Bcl2.
11 . The method of claim 8 , wherein the compound of Formula I is administered in combination with another anti-cancer agent.
12 . The method of claim 11 , wherein the anti-cancer agent is selected from the group consisting of bortezomib, thalidomide, dexamethasone, 5-azacitidine, decitabine, vorinostat, and cyclophosphamide, a PI3K or mTOR inhibitor, rapamycin or a rapamycin analog, a gamma secretase inhibitor, an AMPK inducer, metformin, phenformin, an ornithine decarboxylase inhibitor, and difluoromethylornithine.
13 . The method of claim 7 , wherein the disease or disorder is an autoimmune or inflammatory disease.
14 . The method of claim 7 , wherein the disease or disorder is caused by bacterial or viral infection.
15 . The method of claim 7 , wherein the disease or disorder is AIDS.
16 . The method of claim 7 , wherein the disease or disorder is sepsis.