Conjoint therapies for immunomodulation
The present disclosure relates to methods comprising administering compounds that inhibit VISTA and PD-1 (e.g., PD-1, PD-L1, or PD-L2) pathways with a compound that inhibits TIM-3 and PD-1 (e.g., PD-1, PD-L1, or PD-L2) pathways. The disclosure also relates to treatment of disorders by inhibiting an immunosuppressive signal induced by VISTA, TIM-3, PD-1, PD-L1, and/or PD-L2.
1. A method of modulating an immune response in a subject, comprising administering to the subject an effective amount of an inhibitor of the VISTA pathway and an effective amount of an inhibitor of the TIM-3 pathway, wherein the inhibitor of the VISTA pathway is a compound of formula (I) or a pharmaceutically acceptable salt thereof:
further wherein:
G represents hydrogen or (C 1 -C 6 )alkyl;
R a represents (C 1 -C 6 )alkyl substituted with —OH, —C(O)NR x R y , —NR x R y , guanidino, carboxylic acid, heteroaryl, or aryl-OH;
R a′ represents hydrogen; or R a and R a′ taken together with the atom to which they are attached form a 5- to 6-membered ring;
R b represents (C 1 -C 6 )alkyl, optionally substituted with —OH, —C(O)NR x R y , —NR x R y , carboxylic acid, or heteroaryl; wherein the heteroaryl is optionally further substituted with hydroxyl;
R c represents hydrogen; or R b and R c taken together with the atoms to which they are attached form a 5- to 6-membered ring;
R d represents H, (C 1 -C 6 )alkyl substituted with —OH, —NR x R y , or carboxylic acid;
R e represents hydrogen; or R d and R e taken together with the atoms to which they are attached form a 5- to 6-membered ring optionally containing 1 to 3 heteroatoms selected from O, NH or S; and
R x and R y independently represent hydrogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )acyl, or (C 1 -C 6 )cycloalkyl; or R x and R y taken together with the atom to which they are attached form a 5- to 6-membered ring; and
the inhibitor of the TIM-3 pathway is a compound of formula (II) or a pharmaceutically acceptable salt thereof:
wherein:
Z represents —OH or —NH-G′;
G′ represents hydrogen or (C 1 -C 6 )alkyl;
Y represents hydrogen or a group represented by the following structural formula
R a″ represents (C 1 -C 6 )alkyl substituted with —OH, —NR x R y , —SR x , carboxylic acid, guanidino, or aryl, wherein the aryl group is optionally further substituted with hydroxyl; or R a and G taken together with the atom to which they are attached form a 5- to 6-membered ring containing 1 to 3 heteroatoms selected from O, N or S;
R a′″ represents hydrogen; or R a″ and R a′″ taken together with the atom to which they are attached form a 5- to 6-membered ring, optionally containing 1 to 3 heteroatoms selected from O, N or S;
R b′ represents (C 1 -C 6 )alkyl, optionally substituted with —C(O)NR x′ R y′ , —NR x R y , or carboxylic acid;
R c′ represents hydrogen; or R b′ and R c′ taken together with the atoms to which they are attached form a 5- to 6-membered ring containing 1 to 3 heteroatoms selected from O, N or S, wherein the 5- to 6-membered ring is optionally further substituted with hydroxyl;
R d′ represents (C 1 -C 6 )alkyl, optionally substituted with —OR x′ , carboxylic acid, or aryl-OH; R e′ represents hydrogen; or R d′ and R e′ taken together with the atoms to which they are attached form a 5- to 6-membered ring containing 1 to 3 heteroatoms selected from O, N or S; and
R x′ and R y′ independently represent hydrogen, (C 1 -C 6 )alkyl or (C 2 -C 6 )acyl.
2. The method of claim 1 , wherein G represents hydrogen or methyl.
3. The method of claim 1 , wherein R a represents —(CH 2 ) 2 C(O)OH or (C 1 -C 4 )alkyl, wherein (C 1 -C 4 )alkyl is substituted with —OH, —C(O)NR x R y , —NR x R y , guanidino, heteroaryl, or aryl-OH.
4. The method of claim 1 , wherein R a and R a′ taken together with the atoms to which they are attached form a cyclopentyl ring or cyclohexyl ring.
5. The method of claim 1 , wherein R b represents —CH 2 C(O)OH or (C 1 -C 6 )alkyl, wherein (C 1 -C 6 )alkyl is optionally substituted with —OH, —C(O)NR x R y , or heteroaryl, wherein the heteroaryl is optionally further substituted with hydroxyl.
6. The method of claim 1 , wherein R b and R c taken together with the atoms to which they are attached form a pyrrolidine ring.
7. The method of claim 1 , wherein R d represents —CH 2 OH, —CH(CH 3 )OH, —(CH 2 ) 4 —NH 2 , or —CH 2 C(O)OH.
8. The method of claim 1 , wherein R d and R e taken together with the atoms to which they are attached form a pyrrolidine ring.
9. The method of claim 1 , wherein:
G represents hydrogen or (C 1 -C 6 )alkyl;
R a represents —(CH 2 ) 2 C(O)OH or (C 1 -C 4 )alkyl, wherein (C 1 -C 4 )alkyl is substituted with —OH, —C(O)NR x R y , —NR x R y , guanidino, heteroaryl, or aryl-OH;
R a′ represents hydrogen; or R a and R a′ taken together with the atom to which they are attached form a 5- to 6-membered ring;
R b represents —CH 2 C(O)OH or —(C 1 -C 6 )alkyl, wherein (C 1 -C 6 )alkyl is optionally substituted with —OH, —C(O)NR x R y , —NR x R y , heteroaryl; wherein the heteroaryl is optionally further substituted with hydroxyl;
R c represents hydrogen; or R b and R c taken together with the atoms to which they are attached form a 5- to 6-membered ring;
R d represents H, —(C 1 -C 6 )alkyl substituted with —OH, —NR x R y , or carboxylic acid;
R e represents hydrogen; or R d and R e taken together with the atoms to which they are attached form a 5- to 6-membered ring optionally containing 1 to 3 heteroatoms selected from O, NH or S; and
R x and R y independently represent hydrogen, (C 1 -C 6 )alkyl or (C 2 -C 6 )acyl.
10. The method of claim 1 , wherein the inhibitor of the VISTA pathway is selected from:
a pharmaceutically acceptable salt thereof.
11. The method of claim 1 , wherein Z represents —NH-G′.
12. The method of claim 1 , wherein G′ represents hydrogen or methyl.
13. The method of claim 1 , wherein Z represents —OH.
14. The method of claim 1 , wherein R a″ represents (C 1 -C 4 )alkyl substituted with —OH, —NR x R y′ , —NH—C(═NH)—NH 2 , —SR x′ , carboxylic acid, or aryl, wherein the aryl group is optionally further substituted with hydroxyl.
15. The method of claim 1 , wherein R a″ and G′ taken together with the atoms to which they are attached form a 5- to 6-membered ring containing 1 to 3 heteroatoms selected from O, N or S.
16. The method of claim 1 , wherein R a″ and R a′″ taken together with the atoms to which they are attached form a 5- to 6-membered ring, optionally containing 1 to 3 heteroatoms selected from O, N or S.
17. The method of claim 1 , wherein R b′ represents (C 1 -C 4 )alkyl optionally substituted with —C(O)NR x′ R y′ , —NR x′ R y′ , or carboxylic acid.
18. The method of claim 1 , wherein R b′ and R c′ taken together with the atoms to which they are attached form a 5- to 6-membered ring containing 1 to 3 heteroatoms selected from O, N or S, wherein the 5- to 6-membered ring is optionally further substituted with hydroxyl.
19. The method of claim 1 , wherein Y represents a group represented by the following structural formula
20. The method of claim 1 , wherein R d′ represents (C 1 -C 4 )alkyl, optionally substituted with —OH, —OCH 3 , —C(O)OH, or p-OH(phenyl); and R e′ represents hydrogen.
21. The method of claim 1 , wherein R d′ and R e′ taken together with the atoms to which they are attached form a 5- to 6-membered ring containing 1 to 3 heteroatoms selected from O, N or S.
22. The method of claim 1 , wherein Y represents hydrogen.
23. The method of claim 1 , wherein:
Z represents —OH, or —NH-G′;
G′ represents hydrogen or (C 1 -C 6 )alkyl;
Y represents a group represented by the following structural formula
R a″ represents (C 1 -C 6 )alkyl substituted with —OH, —NH 2 , carboxylic acid, guanidino, or aryl;
R a′″ represents hydrogen; or R a″ and R a′″ taken together with the atom to which they are attached form a 5- to 6-membered ring, optionally containing 1 to 3 heteroatoms selected from O, N or S;
R b′ represents (C 1 -C 6 )alkyl, optionally substituted with —C(O)NR x′ R y′ or carboxylic acid;
R c′ represents hydrogen; or R b′ and R c′ taken together with the atoms to which they are attached form a 5- to 6-membered ring containing 1 to 3 heteroatoms selected from O, N or S;
R d′ represents (C 1 -C 6 )alkyl, optionally substituted with —OR x′ ;
R e′ represents hydrogen; or R d′ and R e′ taken together with the atoms to which they are attached form a 5- to 6-membered ring containing 1 to 3 heteroatoms selected from O, N or S; and
R x′ and R y′ independently represent hydrogen, (C 1 -C 6 )alkyl or (C 2 -C 6 )acyl.
24. The method of claim 1 , wherein the compound that inhibits the TIM-3 pathway is selected from:
a pharmaceutically acceptable salt thereof.
25. The method of claim 1 , wherein the compound that inhibits the VISTA pathway is
or a pharmaceutically acceptable salt thereof.
26. The method of claim 1 , wherein the compound that inhibits the TIM-3 pathway is
or a pharmaceutically acceptable salt thereof.
27. The method of claim 1 , wherein the subject is suffering from a disease or disorder selected from cancer, immune disorders, immunodeficiency disorders, inflammatory disorders, infectious diseases, and transplant rejection; and the method treats the disease or disorder.
28. The method of claim 27 , wherein the disease or disorder is cancer.
29. The method of claim 28 , wherein the cancer is selected from small cell lung cancer, multiple myeloma, bladder carcinoma, primary ductal carcinoma, ovarian carcinoma, Hodgkin's lymphoma, gastric carcinoma, acute myeloid leukemia, and pancreatic cancer.
30. The method of claim 28 , wherein the cancer is selected from blastoma, breast cancer, epithelial cancer, colon cancer, lung cancer, melanoma, prostate cancer, renal cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, uterine cancer, ovarian cancer, colorectal cancer, rectal cancer, cancer of the anal region, cancer of the peritoneum, stomach cancer, testicular cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, cervical cancer, vaginal cancer, vulval cancer, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma, cancer of the urethra, cancer of the penis, chronic or acute leukemia, solid tumors of childhood, Hodgkin's lymphoma, non-Hodgkin's lymphoma, mesothelioma, thymic carcinoma, myeloma, cancer of the bladder, cancer of the ureter, carcinoma of the renal pelvis, liver cancer, pancreatic cancer, post-transplant lymphoproliferative disorder (PTLD), neoplasm of the central nervous system (CNS), tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, epidermoid cancer, salivary gland carcinoma, squamous cell cancer, abnormal vascular proliferation associated with phakomatoses, Meigs' syndrome, Merkel cell carcinoma, and environmentally induced cancers.
31. The method of claim 1 , wherein the compound that inhibits the VISTA pathway is
or a pharmaceutically acceptable salt thereof; and the compound that inhibits the TIM-3 pathway is
or a pharmaceutically acceptable salt thereof.