Methods and compositions for inducing apoptosis by stimulating er stress

Patent metadata

Field	Value
Publication number	US-2016008378-A1
Application number	US-201514614362-A
Country	US
Kind code	A1
Filing date	Feb 4, 2015
Priority date	Mar 26, 2007
Publication date	Jan 14, 2016
Grant date	—

Abstract

The present invention provides a method for inducing apoptosis in selected cells by aggravating ER-stress. The aggravation of ER-stress is achieved in a specific manner by inhibiting SERCA (sarcoplasmic/endoplasmic reticulum calcium ATPase), leading to elevated level of cytoplasmic calcium concentration, yet without inhibiting the activity of COX-2 (cyclooxygenase-2) or triggering the release of histamine. Induction of apoptosis may be enhanced by first inducing or further aggravating ER-stress through inhibition of proteasome or proteases. Also provided are compounds and compositions useful as ER-stress aggravating agents, methods for screening, selecting, identifying and designing the same and methods for treating diseased conditions by inducing apoptosis through specific and selective aggravation of ER-stress.

First claim

1 - 43 . (canceled)

44 . A method of treating a diseased condition in a patient by triggering apoptosis in selected diseased cells, comprising administering a pharmaceutically effective amount of a compound that can induce or aggravate ER stress in the diseased cells by mildly inhibiting SERCA, wherein:
the compound has a general formula:

wherein,
R 1 is methyl, fluoromethyl, difluoromethyl, trifluoromethyl, alkyl, fluoroalkyl, difluoroalkyl, trifluoroalkyl, polyfluoroalkyl, hydroxyalkyl, or carboxyalkyl;
R 2 is hydrogen, fluoro, chloro, bromo; fluoromethyl, difluoromethyl, trifluoromethyl, alkyl, fluoroalkyl, difluoroalkyl, trifluoroalkyl, polyfluoroalkyl, hydroxyalkyl, or carboxyalkyl;
R 3 -R 7 are independently selected from a group consisting of: hydrogen, fluoro, chloro, bromo, alloxy, alkyl, fluoroalkyl, difluoroalkyl, trifluoroalkyl, polyfluoroalkyl, hydroxyalkyl, or carboxyalkyl, aryl and heteroaryl;
R 8 -R 11 are independently selected from a group consisting of: hydrogen, fluoro, chloro, bromo; fluoromethyl, difluoromethyl, trifluoromethyl, alkyl, fluoroalkyl, difluoroalkyl, trifluoroalkyl, polyfluoroalkyl, hydroxyalkyl, carboxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl; and
R 12 is hydrogen, acetyl, acyl, alkyl, fluoroalkyl, difluoroalkyl, trifluoroalkyl, polyfluoroalkyl, hydroxyalkyl, carboxyalkyl; aminoacyl, aminoalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, with the proviso that the compound 4-[5-(4-methylphenyl)-3-(trifluoromethyl)pyrazol-1-yl]benzenesulfonamide is excluded;

45 . The method of claim 44 , wherein R 1 is trifluoromethyl.

46 . The method of claim 44 , wherein R 1 is trifluoromethyl, R 2 , R 4 , R 5 , R 7 R 8 , R 9 , R 10 , and R 11 are hydrogen.

47 . The method of claim 44 , wherein R 3 and R 6 are selected from a group consisting of: fluoro, chloro, bromo; fluoromethyl, difluoromethyl, trifluoromethyl, alkyl, aryl, heteroaryl, fluoroalkyl, difluoroalkyl, trifluoroalkyl, polyfluoroalkyl, hydroxyalkyl, or carboxyalkyl.

48 . The method of claim 44 , wherein the compound is selected from a group consisting of 4-[5-(2,5-di(trifluoromethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide and 4-[5-(2,5-dibromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide or an analogue thereof.

49 . The method of claim 44 , wherein R 12 is aryl or heteroaryl.

50 . The method of claim 49 , wherein the compound is N-(3-aminophenyl)-4-(5-(2,5-dimethylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide.

51 . The method of claim 44 , wherein the compound is not a COX-2 inhibitor or a histamine-release agent.

52 . The method of claim 44 , wherein the compound causes the elevation of cytoplasmic calcium concentration significantly above normal level, so as to cause apoptosis in said diseased cells.

53 . The method of claim 44 , wherein the compound elevates CHOP expression resulting in a condition favorable for initiation of apoptosis in the diseased cells.

54 . The method of claim 44 , wherein said diseased cells are in a state of ER-stress prior to the administrating step.

55 . The method of claim 44 , wherein said diseased condition is caused by apoptosis disregulation.

56 . The method of claim 44 , wherein said diseased condition is cancer.

57 . The method of claim 56 , wherein the cancer is selected from a group consisting of: glioblastoma multiforme, glioma, breast carcinoma, pancreatic carcinoma, Burkett's lymphoma, multiple myeloma, neuroblastoma, prostate cancer, colorectal cancer, recurring cancer, metastatic breast cancer, chemo-resistant tumors, and drug-resistant cancer.

58 . The method of claim 56 , wherein the diseased cells are chemoresistant tumor cells.

59 . The method of claim 56 , wherein the diseased cells are endothelial cells.

60 . The method of claim 56 , wherein the diseased cells are perinecrotic tumor cells.

61 . The method of claim 56 , further comprising the administration of chemotherapy.

62 . The method of claim 61 , wherein the cancer is glioma or glioblastoma multiforme, and the chemotherapy treatment includes temozolomide.

63 . The method of claim 56 , further comprising the administration of radiation therapy.

64 . The method of claim 44 , further comprising administering a pharmaceutically effective amount of a second compound capable of increasing the concentration of misfolded or damaged proteins in the ER.

65 . The method of claim 64 , wherein said second compound is a proteasome inhibitor or a protease inhibitor.

66 . The method of claim 64 , wherein said second compound is selected from a group consisting of: nelfinavir, atazanavir, fosamprenavir, ritonavir, indinavir, or bortezomib or an analogue thereof.

Assignees

• Univ Southern California

Inventors

• Petasis Nicos A
• Hofman Florence M
• Louie Stan G
• Chen Thomas C
• Schonthal Axel H

Classifications

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P35/04

  specific for metastasis · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title