HDAC8 INHIBITORS FOR TREATING CANCER

• US 20190322617A1
• Filed: 05/07/2019
• Published: 10/24/2019
• Est. Priority Date: 08/20/2013
• Status: Active Grant

• Current Assignee: City of Hope, Academia Sinica (Government of The Republic of China), Taipei Medical University WAN Fan Hospital (Government of The Republic of China)
• Original Assignee: City of Hope, Academia Sinica (Government of The Republic of China), Taipei Medical University WAN Fan Hospital (Government of The Republic of China)
• Inventors: Kuo, Ya-Huei, Huang, Wei-Jan, Chang, Chung-I
• Granted Patent: US 11,505,523 B2
• Time in Patent Office: Days
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 259/06 having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07D 209/08 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 209/18 Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 213/56 Amides
• CPC Class Codes: C07D 213/74 Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 215/14 Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 217/16 substituted by oxygen atoms
• CPC Class Codes: C07D 217/20 with oxygen atoms directly attached to the aromatic ring of said aralkyl radical, e.g. papaverine
• CPC Class Codes: C07D 307/91 Dibenzofurans; Hydrogenated dibenzofurans
• CPC Class Codes: C07D 317/60 Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 333/24 Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Abstract

Provided herein, inter alia, are compound and methods of treating cancer by inhibiting HDAC8.

Claims

1-20. -20. (canceled)

21. A method of treating cancer in a subject in need thereof, said method comprising administering an effective amount of an HDAC8 inhibitor to said subject.

22. The method of claim 21, wherein said cancer is a non-mutated p53 cancer.

23. The method of claim 22, wherein said non-mutated p53 cancer is acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), lymphoma, neuroblastoma, glioma, bladder cancer, lung cancer, non-small cell lung cancer, breast cancer, or triple-negative breast cancer.

24. The method of claim 23, wherein said non-mutated p53 cancer is AML.

25. The method of claim 24, wherein said non-mutated p53 cancer has increased HDAC8 activity or HDAC8 expression compared to a mutated p53 cancer.

26. The method of claim 21, wherein said method further comprises prior to said treating, determining whether said cancer in said subject is a non-mutated p53 cancer.

27. The method of claim 26, further comprising determining whether said non-mutated p53 cancer has increased HDAC8 activity or HDAC8 expression.

29. The method of claim 21, wherein said HDAC8 inhibitor is a compound of formula (I):

30. The method of claim 29, wherein said HDAC8 inhibitor is an HDAC8 inhibitor antibody, a HDAC8 inhibitor siRNA, a HDAC8 inhibitor shRNA, or a HDAC8 inhibitor protein.

40. The method of claim 29, wherein R¹ is substituted or unsubstituted C₁-C₄ alkoxy and R² is a substituted or unsubstituted C₄-C₆ aryl.

41. The method of claim 40, wherein R¹ is unsubstituted C₁-C₂ alkoxy and R² is unsubstituted C₆ aryl.

42. The method of claim 29, wherein the compound has formula (II):

28. (canceled)

31. A method of inhibiting HDAC8 mediated deacetylation of p53, said method comprising contacting HDAC8 with a HDAC8 inhibitor in the presence of p53, thereby inhibiting HDAC8 deacetylation of p53.

32. The method of claim 31, wherein said contacting is performed in vitro.

33. The method of claim 31, wherein said contacting is performed in vivo.

34. The method of claim 31, wherein said contacting is performed in an organism.

35. The method of claim 31, wherein said HDAC8 inhibitor is a compound of formula (I):

36. A method of activating p53 in vivo, said method comprising:

(i) contacting a cell with a HDAC8 inhibitor in the presence of HDAC8, wherein the cell is an AML cell; and

(ii) allowing said HDAC8 inhibitor to contact said HDAC8, thereby inhibiting said HDAC8 and activating p53.

37. The method of claim 36, wherein said contacting is performed in an organism.

38. The method of claim 36, wherein said HDAC8 inhibitor is a compound of formula (I):

39. The method of claim 36, wherein the AML cell is an AML stem cell.

43. A method of treating cancer in a subject in need thereof, said method comprising administering an effective amount of an HDAC8 inhibitor compound selected from the group consisting of: