Inhibitors of immune checkpoint modulators and related methods

Abstract

The present disclosure relates to the use MNK-specific inhibitors to inhibit immunosuppression components, such as immune checkpoint proteins PD-1, PD-L1, LAG3, and/or immunosuppressive cytokines, such as IL-10, in order to inhibit or release immune suppression in certain diseases, such as cancer and infectious disease.

1 - 87 . (canceled) 
     
     
         88 . A method of modulating T regulatory (T reg ) cells in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a MNK-specific inhibitor, wherein the MNK-specific inhibitor is a compound according to Formula (I): 
       
         
           
           
               
               
           
         
       
       or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:
 W 1  and W 2  are independently 0, S or N—OR′, where R′ is C 1-4  alkyl; 
 Y is —N(R 5 )—, —O—, —S—, —C(O)—, —S═O, —S(O) 2 —, or —CHR 9 —; 
 R 1  is hydrogen, C 1-4  alkyl, cycloalkyl or heterocyclyl wherein any C 1-4  alkyl, cycloalkyl or heterocyclyl is optionally substituted with 1, 2 or 3 J groups; 
 n is 1, 2 or 3; 
 R 2  and R 3  are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, araalkylene, heteroaryl, heteroarylalkylene, cycloalkyl, cycloalkylalkylene, heterocyclyl, or heterocyclylalkylene, wherein any alkyl, aryl, araalkylene, heteroaryl, heteroarylalkylene, cycloalkyl, cycloalkylalkylene, heterocyclyl, or heterocyclylalkylene, is optionally substituted with 1, 2 or 3 J groups; 
 or R 2  and R 3  taken together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl, wherein any cycloalkyl or heterocyclyl is optionally substituted with 1, 2 or 3 J groups; 
 R 4a  and R 4b  are each independently hydrogen, halogen, hydroxyl, thiol, hydroxyalkylene, cyano, alkyl, alkoxy, acyl, thioalkyl, alkenyl, alkynyl, cycloalkyl, aryl, or heterocyclyl; 
 R 5  is hydrogen, cyano, or C 1-4  alkyl; 
 or R 5  and R 8  taken together with the atoms to which they are attached form a fused heterocyclyl optionally substituted with 1, 2 or 3 J groups; 
 R 6 , R 7  and R g  are each independently hydrogen, hydroxy, halogen, cyano, amino, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkylene, cycloalkylalkenylene, alkylaminyl, alkylcarbonylaminyl, cycloalkylcarbonylaminyl, cycloalkylalkylaminyl, heterocyclylaminyl, heteroaryl, or heterocyclyl, and wherein any amino, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkylene, cycloalkylalkenylene, amino, alkylaminyl, alkylcarbonylaminyl, cycloalkylcarbonyl aminyl, cycloalkylaminyl, heterocyclylaminyl, heteroaryl, or heterocyclyl is optionally substituted with 1, 2 or 3 J groups; 
 or R 7  and R 8  taken together with the atoms to which they are attached form a fused heterocyclyl or heteroaryl optionally substituted with 1, 2 or 3 J groups; 
 J is —SH, —SR 9 , —S(O)R 9 , —S(O) 2 R 9 , —S(O)NH 2 , —S(O)NR 9 R 9 , —NH 2 , —NR 9 R 9 , —COOH, —C(O)OR 9 , —C(O)R 9 , —C(O)—NH 2 , —C(O)—NR 9 R 9 , hydroxy, cyano, halogen, acetyl, alkyl, C 1-4  alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, thioalkyl, cyanoalkylene, alkylaminyl, NH 2 —C(O)— alkylene, NR 9 R 9 —C(O)-alkylene, —CHR 9 —C(O)—C 1-4  alkyl, —C(O)—C 1-4  alkyl, alkylcarbonylaminyl, cycloalkyl, cycloalkylalkylene, cycloalkylalkenylene, cycloalkylcarbonylaminyl, cycloalkylaminyl, —CHR 9 —C(O)-cycloalkyl, —C(O)-cycloalkyl, —CHR 9 —C(O)-aryl, —CHR 9 -aryl, —C(O)-aryl, —CHR 9 —C(O)-heterocycloalkyl, —C(O)-heterocycloalkyl, heterocyclylaminyl, or heterocyclyl; or any two J groups bound to the same carbon or hetero atom may be taken together to form oxo; and 
 
       R 9  is hydrogen, C 1-4  alkyl or —OH, 
       wherein administering the MNK-specific inhibitor leads to a reduction in the number of T reg  cells compared to the number of T reg  cells in the absence of the MNK-specific inhibitor. 
     
     
         89 . The method of  claim 88 , wherein the subject has a disease associated with immune resistance. 
     
     
         90 . The method of  claim 89 , wherein the disease associated with immune resistance is a cancer or an infection. 
     
     
         91 . The method of  claim 90 , wherein the infection is a viral, bacterial, fungal, or parasitic infection. 
     
     
         92 . The method of  claim 91 , wherein the viral infection is an infection by a flavivirus, herpes virus, hepatitis virus, papillomavirus, paramyxovirus, retrovirus, lentivirus, or varicella-zoster virus. 
     
     
         93 . The method of  claim 91 , wherein the viral infection is an infection by a hepatitis C virus (HCV), hepatitis B virus (HBV), hepatitis A virus, hepatitis E virus, Japanese encephalitis virus, or human immunodeficiency virus (HIV). 
     
     
         94 . The method of  claim 90 , wherein the cancer is a solid tumor, melanoma, non-small cell lung cancer, renal cell carcinoma, renal cancer, a hematological cancer, prostate cancer, castration-resistant prostate cancer, colon cancer, rectal cancer, gastric cancer, esophageal cancer, bladder cancer, head and neck cancer, thyroid cancer, breast cancer, triple-negative breast cancer, ovarian cancer, cervical cancer, lung cancer, urothelial cancer, pancreatic cancer, glioblastoma, hepatocellular cancer, myeloma, multiple myeloma, leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, myelodysplastic syndrome, brain cancer, CNS cancer, malignant glioma, or any combination thereof. 
     
     
         95 . The method of  claim 94 , wherein the reduction in the number of T reg  cells occurs in a population of tumor infiltrating lymphocytes (TILs) in a tumor in the subject. 
     
     
         96 . The method of  claim 95 , wherein reducing the number of T reg  cells abrogates antitumor immunity through the T reg  cells. 
     
     
         97 . The method of  claim 96 , wherein reducing the number of T reg  cells increases ratio of T effector (T E ) cells to T reg  cells (T E :T reg  ratio) present in the population of TILs in the tumor. 
     
     
         98 . The method of  claim 95 , wherein the number of T reg  cells is determined by counting CD4 + /FOXP3 +  cells present in the population of TILs in the tumor. 
     
     
         99 . The method of  claim 97 , wherein the number of T E  cells is determined by counting CD3 + /CD8 +  cells present in the population of TILs in the tumor. 
     
     
         100 . The method of  claim 97 , wherein the average T E :T reg  ratio present in the population of TILs in the tumor increases from about 3.4 prior to treatment with the MNK-specific inhibitor to about 9.7 after treatment with the MNK-specific inhibitor. 
     
     
         101 . The method of  claim 100 , wherein the increased T E :T reg  ratio induces expression of a MHC or a HLA class II molecule. 
     
     
         102 . The method of  claim 100 , wherein the increased T E :T reg  ratio allows the T E  cells to clear pathogenic cells. 
     
     
         103 . The method of  claim 88 , wherein the method further comprises administering a therapy that induces or enhances an anti-cancer response. 
     
     
         104 . The method of  claim 103 , wherein the therapy that induces or enhances an anti-cancer response is a vaccine, an inhibitor of an immunosuppression component, a B-Raf inhibitor, a MEK inhibitor, a VEGF inhibitor, a VEGFR inhibitor, a tyrosine kinase inhibitor, a cytotoxic agent, a chemotherapeutic, or any combination thereof. 
     
     
         105 . The method of  claim 104 , wherein the therapy that induces or enhances an anti-cancer response is an inhibitor of an immunosuppression component, wherein the inhibitor of an immunosuppression component is an antibody specific for PD-1, PD-L1, CLA4, or any combination thereof, wherein the antibody specific for PD-1 is pidilizumab, nivolumab, pembrolizumab, MK-3475, or any combination thereof, wherein the antibody specific for PD-L1 is MDX-1105, BMS-936559, durvalumab (MEDI4736), atezolizumab (MPDL3280A), MSB0010718C, or any combination thereof, and wherein the antibody specific for CTLA4 is tremelimumab, ipilimumab, or both. 
     
     
         106 . The method of  claim 104 , wherein the therapy that induces or enhances an anti-cancer response is a chemotherapeutic, wherein the chemotherapeutic is selected from the group consisting of vemurafenib, dabrafenib, trametinib, cobimetinib, sunitinib, erlotinib, paclitaxel, docetaxel, and any combination thereof. 
     
     
         107 . A method of modulating T regulatory (T reg ) cells in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a MNK-specific inhibitor, wherein the MNK-specific inhibitor is a compound: 
       
         
           
           
               
               
           
         
       
       or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein administering the MNK-specific inhibitor leads to a reduction in the number of T reg  cells compared to the number of T reg  cells in the absence of the MNK-specific inhibitor.