HDAC inhibitors, alone or in combination with BTK inhibitors, for treating chronic lymphocytic leukemia

Patent metadata

Field	Value
Publication number	US-11813261-B2
Application number	US-201716093278-A
Country	US
Kind code	B2
Filing date	Apr 19, 2017
Priority date	Apr 19, 2016
Publication date	Nov 14, 2023
Grant date	Nov 14, 2023

Abstract

Disclosed are histone deacetylase (HDAC) inhibitors, or combinations comprising an HDAC inhibitor and a Bruton's tyrosine kinase (BTK) inhibitor, for the treatment of chronic lymphocytic leukemia in a subject in need thereof. Also provided herein are methods for treating chronic lymphocytic leukemia in a subject in need thereof comprising administering to the subject a therapeutically effective amount of an HDAC inhibitor, or a combination comprising an HDAC inhibitor and a BTK inhibitor. Other related methods are disclosed.

First claim

The invention claimed is:

1. A method for treating chronic lymphocytic leukemia in a subject in need thereof comprising administering to the subject a therapeutically effective amount of
(a) a histone deacetylase 6 (HDAC6) selective inhibitor, wherein the HDAC6 inhibitor is Compound B:

or a pharmaceutically acceptable salt thereof; and
(b) a Bruton's tyrosine kinase (BTK) inhibitor or a pharmaceutically acceptable salt thereof;
wherein the BTK inhibitor is ibrutinib or a pharmaceutically acceptable salt thereof;
the HDAC6 selective inhibitor and the BTK inhibitor are each administered in a sub-therapeutically effective amount;
the HDAC6 selective inhibitor and the BTK inhibitor reduce the expression of an inhibitory checkpoint molecule in a T- and/or B-cell compartment in the subject;
wherein the checkpoint molecule is selected from the group consisting of CD274 (PDL-1), CD273 (PDL-2), CD80 (87-1), CD86 (B7-2), CD 152 (CTLA4), CD275 (B7RP1), CD276 (B7-H3), B7-H4 (VTCN1), CD270 (HVEM), BLTA, GAL9, CD366 (TIMS), A2aR, CD279 (PD-1), KIR, and CD223 (LAGS); and
the ratio of Compound B to the BTK inhibitor is 3:1.

2. The method of claim 1 , wherein the HDAC6 selective inhibitor and the BTK inhibitor are in the same formulation.

3. The method of claim 1 , wherein the HDAC6 selective inhibitor and the BTK inhibitor are in separate formulations.

4. The method of claim 1 , wherein the HDAC6 selective inhibitor and the BTK inhibitor are administered at the same time.

5. The method of claim 1 , wherein the HDAC6 selective inhibitor and the BTK inhibitor are administered at different times.

6. The method of claim 1 , wherein checkpoint molecules are CD274 (PDL-1) and CD273 (PDL-2).

7. The method of claim 1 , wherein the checkpoint molecule is reduced on regulatory T lymphocytes (Tregs).

8. The method of claim 7 , wherein the T lymphocytes are CD4+ or CD8+.

Assignees

• Acetylon Pharmaceuticals Inc
• H Lee Moffitt Cancer Ct & Res

Inventors

• Jones Simon S
• Quayle Steven N
• Sahakian Eva
• Ibarz Javier Pinilla

Classifications

• A61K31/505 Primary

  Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• A61K45/06

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

• A61P35/00

  Antineoplastic agents · CPC title

• C07D239/42

  One nitrogen atom (nitro radicals C07D239/30) · CPC title