Compositions and methods for modulating HEXIM1 expression

Patent metadata

Field	Value
Publication number	US-11833124-B2
Application number	US-202117217084-A
Country	US
Kind code	B2
Filing date	Mar 30, 2021
Priority date	Jan 30, 2014
Publication date	Dec 5, 2023
Grant date	Dec 5, 2023

Abstract

A method of inducing HEXIM1 expression in cells of a subject includes administering to the cells a compound having the formula,

and pharmaceutically acceptable salts thereof.

First claim

Having described the invention, we claim:

1. A method of treating cancer in a subject in need thereof, the method comprising administering to cancer cells of the subject a therapeutically effective amount of a compound having the formula:

wherein R 2 is selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 3 -C 20 aryl, heterocycloalkenyl containing from 5-6 ring atoms, heteroaryl or heterocyclyl containing from 5-14 ring atoms, C 6 -C 24 alkaryl, C 6 -C 24 aralkyl, halo, silyl, hydroxyl, sulfhydryl, C 1 -C 24 alkoxy, C 2 -C 24 alkenyloxy, C 2 -C 24 alkynyloxy, C 5 -C 20 aryloxy, acyl, acyloxy (—O-acyl), C 2 -C 24 alkoxycarbonyl (—(CO)—O-alkyl), C 6 -C 20 aryloxycarbonyl (—(CO)—O-aryl), C 2 -C 24 alkylcarbonato (—O—(CO)—O-alkyl), C 6 -C 20 arylcarbonato (—O—(CO)—O-aryl), carboxy (—COOH), carboxylato (—COO − ), carbamoyl (—(CO)—NH 2 ), C 1 -C 24 alkyl-carbamoyl (—(CO)—NH(C 1 -C 24 alkyl)), arylcarbamoyl (—(CO)—NH-aryl), thiocarbamoyl (—(CS)—NH 2 ), carbamido (—NH—(CO)—NH 2 ), cyano (—CN), isocyano (—N + C − ), cyanato (—O—CN), isocyanato (—O—N + ═C − ), isothiocyanato (—S—CN), azido (—N═N + ═N − ), formyl (—(CO)—H), thioformyl (—(CS)—H), amino (—NH 2 ), C 1 -C 24 alkyl amino, C 5 -C 20 aryl amino, C 2 -C 24 alkylamido (—NH—(CO)-alkyl), C 6 -C 20 arylamido (—NH—(CO)-aryl), sulfanamido, imino, alkylimino, arylimino, nitro (—NO 2 ), nitroso (—NO), sulfo (—SO 2 —OH), sulfonato (—SO 2 —O − ), C 1 -C 24 alkylsulfanyl, arylsulfanyl, C 1 -C 24 alkylsulfinyl (—(SO)-alkyl), C 5 -C 20 arylsulfinyl (—(SO)-aryl), C 1 -C 24 alkylsulfonyl (—SO 2 -alkyl), C 5 -C 20 arylsulfonyl (—SO 2 -aryl), sulfonamide, phosphono (—P(O)(OH) 2 ), phosphonato (—P(O)(O − ) 2 ), phosphinato (—P(O)(O − )), phospho (—PO 2 ), phosphino (—PH 2 ), polyalkyl ethers (—[(CH 2 ) n O] m ), phosphates, and phosphate esters;
R 3 and R 4 are the same or different and selected from the group consisting of hydrogen and substituted or unsubsubstituted C 1 -C 6 alkyl;
R 5 is selected from the group consisting of a substituted or unsubstituted C 2 -C 6 alkylene, C 2 -C 24 alkenylene, C 2 -C 24 alkynylene, C 3 -C 20 arylene, heterocycloalkenylene containing from 5-6 ring atoms, heteroarylene or heterocyclylene containing from 5-14 ring atoms, C 6 -C 24 alkarylene, and C 6 -C 24 aralkylene;
wherein R 6 is selected from the group consisting of substituted or unsubstituted C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 3 -C 20 aryl, heterocycloalkenyl containing from 5-6 ring atoms, heteroaryl or heterocyclyl containing from 5-14 ring atoms, C 6 -C 24 alkaryl, C 6 -C 24 aralkyl, C 1 -C 24 alkoxy, C 2 -C 24 alkenyloxy, C 2 -C 24 alkynyloxy, C 5 -C 20 aryloxy, acyl, acyloxy (—O-acyl), C 2 -C 24 alkoxycarbonyl (—(CO)—O-alkyl), C 6 -C 20 aryloxycarbonyl (—(CO)—O-aryl), C 2 -C 24 alkylcarbonato (—O—(CO)—O-alkyl), C 6 -C 20 arylcarbonato (—O—(CO)—O-aryl), carboxy (—COOH), carboxylato (—COO − ), carbamoyl ((CO)—NH 2 ), C 1 -C 24 alkyl-carbamoyl (—(CO)—NH(C 1 -C 24 alkyl)), and arylcarbamoyl (CO)—NH-aryl);
R 6 is not a methyl group if R 5 is 1,6-hexylene, R 2 is an acetyl group, and R 3 and R 4 are hydrogen; and pharmaceutically acceptable salts thereof.

2. The method of claim 1 , wherein the therapeutically effective amount is an amount effective to induce HEXIM1 expression in the cancer cells of the subject.

3. The method of claim 1 , wherein the therapeutically effective amount is an amount effective to induce differentiation of the cancer cells.

4. The method of claim 1 , wherein the cancer cells are metastatic cancer cells and the compound is administered to the metastatic cancer cells at an amount effective to inhibit at least one of cancer cell invasion, angiogenesis, and/or pre-metastatic niche formation.

5. The method of claim 1 , wherein the compound exhibits negligible inhibition of histone diacetylene (HDAC) activity.

6. The method of claim 1 , wherein the compound is administered to the subject as a pharmaceutical composition that includes the compound and the pharmaceutically acceptable carrier and the pharmaceutical composition administered to the subject induces HEXIM1 expression in the cancer cells without promoting thrombocytopenia in the subject.

7. The method of claim 1 , wherein R 2 is selected from the group consisting of substituted or unsubstituted alkanesulfonyl, alkanesulfinyl, alkanoyl, benzoyl, and aroyl.

8. The method of claim 1 , wherein R 5 is selected from the group consisting of propylene, butylene, pentylene, hexylene, heptylene, octylene, nonylene, dodecylene, cyclohexylene, 1,4-cylohexylene-bis(methylene), 1,4-cylohexylene-bis(ethylene), 1,4-cylohexylene-bis(propylene), phenylene, 1,4-phenylene-bis(methylene), 1,4-phenylene-bis(ethylene), and 1,4-phenylene-bis(propylene).

9. The method of claim 1 , wherein the compound has the formula:

wherein R 6 and R 7 are the same or different and are selected from the group consisting of substituted or unsubstituted C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 3 -C 20 aryl, heterocycloalkenyl containing from 5-6 ring atoms, heteroaryl or heterocyclyl containing from 5-14 ring atoms, C 6 -C 24 alkaryl, C 6 -C 24 aralkyl, C 1 -C 24 alkoxy, C 2 -C 24 alkenyloxy, C 2 -C 24 alkynyloxy, C 5 -C 20 aryloxy, acyl, acyloxy (—O-acyl), C 2 -C 24 alkoxycarbonyl (—(CO)—O-alkyl), C 6 -C 20 aryloxycarbonyl (—(CO)—O-aryl), C 2 -C 24 alkylcarbonato (—O—(CO)—O-alkyl), C 6 -C 20 arylcarbonato (—O—(CO)—O-aryl), carboxy (—COOH), carboxylato (—COO − ), carbamoyl (—(CO)—NH 2 ), C 1 -C 24 alkyl-carbamoyl (—(CO)—NH(C 1 -C 24 alkyl)),and arylcarbamoyl (—(CO)—NH-aryl);
at least one of R 6 or R 7 is not a methyl group if R 5 is 1,6-hexylene and R 3 and R 4 are hydrogen; and pharmaceutically acceptable salts thereof.

10. The method of claim 1 , wherein the compound has the formula:

wherein R 6 and R 7 are the same or different and are selected from the group consisting of substituted or unsubstituted C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 3 -C 20 aryl, heterocycloalkenyl containing from 5-6 ring atoms, heteroaryl or heterocyclyl containing from 5-14 ring atoms, C 6 -C 24 alkaryl, C 6 -C 24 aralkyl, C 1 -C 24 alkoxy, C 2 -C 24 alkenyloxy, C 2 -C 24 alkynyloxy, C 5 -C 20 aryloxy, acyl, acyloxy (—O-acyl), C 2 -C 24 alkoxycarbonyl (—(CO)—O-alkyl), C 5 -C 20 aryloxycarbonyl (—(CO)—O-aryl), C 2 -C 24 alkylcarbonato (—O—(CO)—O-alkyl), C 6 -C 20 arylcarbonato (—O—(CO)—O-aryl), carboxy (—COOH), carboxylato (—COO − ), carbamoyl (—(CO)—NH 2 ), C 1 -C 24 alkyl-carbamoyl (—(CO)—NH(C 1 -C 24 alkyl)),and arylcarbamoyl (—(CO)—NH-aryl);
at least one of R 6 or R 7 is not a methyl group if R 5 is 1,6-hexylene; and pharmaceutically acceptable salts thereof.

11. The method of claim 9 , wherein R 6 and R 7 are the same.

12. The method of claim 9 , wherein R 6 and R 7 are different.

13. The method of claim 10 , wherein R 6 is a substituted or unsubstituted C 1 -C 24 alkyl and R 7 is selected from the group consisting of substituted or unsubstituted C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 3 -C 20 aryl, heterocycloalkenyl containing from 5-6 ring atoms, heteroaryl or heterocyclyl containing

Assignees

• Univ Case Western Reserve
• Cleveland State Univ

Inventors

• Su Bin
• Montano Monica M

Classifications

• A61K31/18 Primary

  Sulfonamides (compounds containing a para-N-benzene-sulfonyl-N- group A61K31/63) · CPC title

• A61K31/16 Primary

  Amides, e.g. hydroxamic acids · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title