Increasing expression of interferon regulated genes with combinatons of histone deacetylase inhibitors and immunomodulatory drugs

Abstract

Provided herein is a combination comprising an HDAC inhibitor and an IMiD for increasing interferon regulated gene expression or decreasing c-MYC gene expression in a cancer cell or tumor in a subject in need thereof. Increasing interferon regulated gene expression may result in increased recognition of tumors by innate or adaptive immune system and an increase in programmed cell death (apoptosis) gene expression, increasing apoptosis in cancer cells and tumors. The cells can be multiple myeloma cells or diffuse large B-cell lymphoma cells. Also provided are methods for treating myelodysplastic syndromes/acute myeloid leukemia (MDS/AML) or pathogen infections in a subject in need thereof comprising administering to the subject an effective amount of HDAC inhibitor and an IMiD. The HDAC inhibitor can be an HDAC6-selective inhibitor.

1 . A method for increasing the expression of interferon-regulated genes in cancer cells comprising co-administering a therapeutically effective amount of a histone deacetylase 6 (HDAC6)-selective inhibitor and an immunomodulatory drug (IMiD) to a subject in need thereof, wherein the HDAC6-selective inhibitor is a compound of Formula II: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein, 
         R x  and R y  together with the carbon to which each is attached, form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl; 
         each R A  is independently C 1-6 alkyl, C 1-6 -alkoxy, halo, OH, —NO 2 , —CN, or —NH 2 ; and 
         m is 0 or 1; and 
         wherein the IMiD is 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; or 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; and 
         wherein the interferon is interferon gamma or alpha. 
       
     
     
         2 . The method of  claim 1 , wherein the co-administration of the HDAC6-selective inhibitor and the IMiD results in a synergistic increase in the expression of genes regulated by interferon in the cancer cells. 
     
     
         3 . (canceled) 
     
     
         4 . (canceled) 
     
     
         5 . (canceled) 
     
     
         6 . (canceled) 
     
     
         7 . (canceled) 
     
     
         8 . The method of  claim 1 , wherein the cancer cells are multiple myeloma cells, diffuse large B-cell lymphoma cells, indolent lymphoma cells, follicular lymphoma cells, chronic lymphocytic leukemia cells, or mantle cell lymphoma cells. 
     
     
         9 . The method of  claim 8 , wherein the multiple myeloma is a relapsed or refractory multiple myeloma. 
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . The method of  claim 1 , wherein the co-administration of the HDAC6-selective inhibitor and the IMiD enhances the recognition of the cancer cells by the subject's immune system. 
     
     
         13 . The method of  claim 12 , wherein the increased recognition of cancer cells by the immune system comprises increased migration of T cells to the cancer cells. 
     
     
         14 . The method of  claim 1 , wherein the co-administration of the HDAC6-selective inhibitor and the IMiD increases the expression of at least one gene selected from the group consisting of one or more major histocompatibility complex (HLA) genes, C—C motif chemokine 4 (CCL4; MIP-1p), caspase-1 (CASP1), interferon α-inducible protein 27 (IF127), interferon-induced protein with tetratricopeptide repeats 1 (IFIT1), interferon-induced protein with tetratricopeptide repeats 3 (IFIT3), poly (ADP-ribose) polymerase family member 14 (PARP 14), and XIAP-associated factor 1 (XAF1). 
     
     
         15 . (canceled) 
     
     
         16 . (canceled) 
     
     
         17 . (canceled) 
     
     
         18 . The method of  claim 1 , wherein the co-administration of the HDAC6-selective inhibitor and the IMiD acts in synergy with a chemotherapeutic agent or an immunotherapeutic agent to increase the apoptosis of the cancer cells. 
     
     
         19 . (canceled) 
     
     
         20 . The method of  claim 1 , wherein the subject has a lymphocyte proliferation disorder, and wherein the co-administration increases the expression of interferon-regulated genes and treats the lymphocyte proliferative disorder. 
     
     
         21 . (canceled) 
     
     
         22 . (canceled) 
     
     
         23 . (canceled) 
     
     
         24 . (canceled) 
     
     
         25 . The method of  claim 1 , wherein the co-administration of the HDAC6-selective inhibitor and the IMiD inhibits BIRC5 (survivin) gene expression in the cancer cells. 
     
     
         26 . A method for decreasing the expression of c-myc targeted genes in cancer cells comprising co-administering a therapeutically effective amount of a histone deacetylase 6 (HDAC6)-selective inhibitor and an immunomodulatory drug (IMiD) to a subject in need thereof, wherein the co-administration of the HDAC6-selective inhibitor and the IMiD results in a synergistic reduction in the expression of c-myc target genes in the cancer cells, wherein the HDAC6-selective inhibitor is a compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein, 
         ring B is aryl or heteroaryl; 
         R 1  is an aryl or heteroaryl, each of which may be optionally substituted by OH, halo, or C 1-6 -alkyl; 
         and 
         R is H or C 1-6 -alkyl; and 
         wherein the IMiD is 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; or 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         27 . A method of treating an infection by a pathogen comprising co-administering a therapeutically effective amount of an HDAC6-selective inhibitor and an IMiD to a subject in need thereof, wherein the infection is treated, wherein the HDAC6-selective inhibitor is a compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein, 
         ring B is aryl or heteroaryl; 
         R 1  is an aryl or heteroaryl, each of which may be optionally substituted by OH, halo, or C 1-6 -alkyl; 
         and 
         R is H or C 1-6 -alkyl; and 
         wherein the IMiD is 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof: or 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         28 . (canceled) 
     
     
         29 . The method of  claim 26 , wherein the subject has a disease or disorder selected from the group consisting of: multiple myeloma, breast cancer, colorectal cancer, T cell leukemia, pancreatic cancer, gastric cancer, lymphoma, ovarian cancer, prostate cancer, lung cancer, medulloblastoma, melanoma, and uterine cancer. 
     
     
         30 . The method of  claim 1 , wherein the subject has a disease or disorder having interferon sensitivity. 
     
     
         31 . (canceled) 
     
     
         32 . (canceled) 
     
     
         33 . (canceled) 
     
     
         34 . (canceled) 
     
     
         35 . (canceled) 
     
     
         36 . (canceled) 
     
     
         37 . The method of  claim 1 , wherein the compound of Formula II is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof or 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         38 . (canceled) 
     
     
         39 . (canceled) 
     
     
         40 . (canceled) 
     
     
         41 . (canceled) 
     
     
         42 . (canceled) 
     
     
         43 . (canceled) 
     
     
         44 . (canceled) 
     
     
         45 . A method for increasing the expression of interferon-regulated genes in multiple myeloma cells comprising co-administering a therapeutically effective amount of a selective histone deacetylase 6 (HDAC6)-6-selective inhibitor and lenalidomide or pomalidomide to a subject in need thereof, wherein the HDAC6-selective inhibitor is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof: or 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         46 . (canceled) 
     
     
         47 . (canceled) 
     
     
         48 . (canceled) 
     
     
         49 . (canceled) 
     
     
         50 . (canceled) 
     
     
         51 . The method of  claim 46 , wherein the co-administration of the HDAC6-selective inhibitor and lenalidomide or pomalidomide acts in synergy with a chemotherapeutic agent or an immunotherapeutic agent to increase the apoptosis of the multiple myeloma cells. 
     
     
         52 . (canceled) 
     
     
         53 . The method of  claim 46 , wherein the interferon-regulated genes comprise at least one gene selected from the group consisting of a C—C motif chemokine 4 (CCL4; MIP-1p), caspase-1 (CASP1), interferon α-inducible protein 27 (IF127), an interferon-induced protein with tetratricopeptide repeats 1 (IFIT1), an interferon-induced protein with tetratricopeptide repeats 3 (IFIT3), a poly (ADP-ribose) polymerase family member 14 (PARP 14), and XIAP-associated factor 1 (XAF1). 
     
     
         54 . (canceled) 
     
     
         55 . (canceled) 
     
     
         57 . The method of  claim 26 , wherein the compound of Formula I is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; or 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         58 . The method of  claim 27 , wherein the compound of Formula I is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; or 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof.