US 11,813,261 B2
HDAC inhibitors, alone or in combination with BTK inhibitors, for treating chronic lymphocytic leukemia
Simon S. Jones, Harvard, MA (US); Steven N. Quayle, Brookline, MA (US); Eva Sahakian, Tampa, FL (US); and Javier Pinilla Ibarz, Tampa, FL (US)
Assigned to ACETYLON PHARMACEUTICALS, INC., Summit, NJ (US); and H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE, INC., Tampa, FL (US)
Appl. No. 16/093,278
Filed by ACETYLON PHARMACEUTICALS, INC., Summit, NJ (US); and H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE, INC., Tampa, FL (US)
PCT Filed Apr. 19, 2017, PCT No. PCT/US2017/028435
§ 371(c)(1), (2) Date Oct. 12, 2018,
PCT Pub. No. WO2017/184774, PCT Pub. Date Oct. 26, 2017.
Claims priority of provisional application 62/324,733, filed on Apr. 19, 2016.
Prior Publication US 2019/0209559 A1, Jul. 11, 2019
Int. Cl. A61K 31/505 (2006.01); A61K 31/519 (2006.01); C07D 239/42 (2006.01); A61K 45/06 (2006.01); A61P 35/00 (2006.01)
CPC A61K 31/505 (2013.01) [A61K 31/519 (2013.01); A61K 45/06 (2013.01); A61P 35/00 (2018.01); C07D 239/42 (2013.01); A61K 2300/00 (2013.01)] 8 Claims
 
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:

OG Complex Work Unit Chemistry
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.