Combination therapies of HDAC inhibitors and PD-1 inhibitors

1. A method for treating cancer comprising administering a therapeutically effective amount of a histone deacetylase inhibitor (HDAC inhibitor) in combination with a PD-1 inhibitor to a subject in need of treatment and whose cancer has been previously treated with a PD-L1 inhibitor, wherein the PD-1 inhibitor is an antibody PD-1 inhibitor, and the HDAC inhibitor is a compound of formula I:

or a pharmaceutically acceptable salt thereof,

wherein,

A is phenyl or a heterocyclic group, optionally substituted with 1 to 4 substituents selected from the group consisting of halogen, —OH, —NH 2 , —NO 2 , —CN, —COOH, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 aminoalkyl, C 1 -C 4 alkylamino, C 2 -C 4 acyl, C 2 -C 4 acylamino, C 1 -C 4 alkythio, C 1 -C 4 perfluoroalkyl, C 1 -C 4 perfluoroalkyloxy, C 1 -C 4 alkoxycarbonyl, phenyl, and a heterocyclic group;

B is phenyl optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, —OH, —NH 2 , —NO 2 , —CN, —COOH, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 aminoalkyl, C 1 -C 4 alkylamino, C 2 -C 4 acyl, C 2 -C 4 acylamino, C 1 -C 4 alkylthio, C 1 -C 4 perfluoroalkyl, C 1 -C 4 perfluoroalkyloxy, C 1 -C 4 alkoxycarbonyl, and phenyl;

Y is —C(O)NH—CH 2 —;

Z is a bond or C 1 -C 4 alkylene, —O—, —S—, —NH—, —CO—, —CS—, —SO—, or —SO 2 —;

R 1 and R 2 are independently hydrogen or C 1 -C 4 alkyl;

R 3 is hydrogen or C 1 -C 4 alkyl;

R 4 is hydrogen or —NH 2 ;

one of X 1 , X 2 , X 3 , or X 4 is halogen, —OH, —NH 2 , —NO 2 , —CN, —COOH, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 aminoalkyl, C 1 -C 4 alkylamino, C 2 -C 4 acyl, C 2 -C 4 acylamino, C 1 -C 4 alkylthio, C 1 -C 4 perfluoroalkyl, C 1 -C 4 perfluoroalkyloxy, or C 1 -C 4 alkoxycarbonyl optionally substituted with halogen or C 1 -C 4 alkyl, while the others of X 1 , X 2 , X 3 , or X 4 are independently hydrogen,

provided, however, that when R 4 is hydrogen, one of X 1 , X 2 , X 3 , or X 4 is —NH 2 , an aminoalkyl group or an alkylamino group.

2. The method according to claim 1 , wherein the cancer after treatment with PD-L1 inhibitor resulted in partial response, but later develops resistance to PD-L1 with progression of disease.

3. The method according to claim 1 , wherein the cancer after treatment with PD-L1 inhibitor resulted in stable disease, but later develops resistance to PD-L1 with progression of disease.

4. The method according to claim 1 , wherein the cancer after treatment with PD-L1 inhibitor resulted in a complete response, but later develops resistance to PD-L1 with progression of disease.

5. The method according to claim 1 , wherein the cancer after treatment with PD-L1 inhibitor resulted in no response to treatment.

6. The method according to claim 1 , wherein the antibody PD-1 inhibitor is nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680.

7. The method of claim 1 , wherein the HDAC inhibitor is a compound of the following formula

8. The method of claim 1 , wherein the cancer treated is one or more of skin cancer, ovarian cancer; cancers of heart, placenta, and skeletal muscle; breast cancer; cancers of the head and neck, lymphomas, mantle cell lymphoma, non-Hodgkins B cell lymphoma, PTCL, adenoma, squamous cell carcinoma, laryngeal carcinoma, salivary carcinoma, thymomas and thymic carcinoma; leukemia; cancers of the retina; cancers of the esophagus; multiple myeloma; melanoma; colorectal cancer; lung cancer; cervical cancer; endometrium carcinoma; gallbladder cancer; liver cancer; thyroid follicular cancer; gastric cancer; non-small cell lung carcinoma; glioma; urothelial cancer; bladder cancer; prostate cancer; renal cell cancer; infiltrating ductal carcinoma; and glioblastoma multiform.

9. A method for reducing metastasis of a primary tumor in a subject, wherein said method comprises administering a therapeutically effective amount of a histone deacetylase inhibitor (HDAC inhibitor) in combination with a PD-1 inhibitor to the subject, wherein the PD-1 inhibitor is an antibody PD-1 inhibitor, and the HDAC inhibitor is a compound of formula I:

or a pharmaceutically acceptable salt thereof,

wherein,

A is phenyl or a heterocyclic group, optionally substituted with 1 to 4 substituents selected from the group consisting of halogen, —OH, —NH 2 , —NO 2 , —CN, —COOH, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 aminoalkyl, C 1 -C 4 alkylamino, C 2 -C 4 acyl, C 2 -C 4 acylamino, C 1 -C 4 alkythio, C 1 -C 4 perfluoroalkyl, C 1 -C 4 perfluoroalkyloxy, C 1 -C 4 alkoxycarbonyl, phenyl, and a heterocyclic group;

B is phenyl optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, —OH, —NH 2 , —NO 2 , —CN, —COOH, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 aminoalkyl, C 1 -C 4 alkylamino, C 2 -C 4 acyl, C 2 -C 4 acylamino, C 1 -C 4 alkylthio, C 1 -C 4 perfluoroalkyl, C 1 -C 4 perfluoroalkyloxy, C 1 -C 4 alkoxycarbonyl, and phenyl;

Y is —C(O)NH—CH 2 —;

Z is a bond or C 1 -C 4 alkylene, —O—, —S—, —NH—, —CO—, —CS—, —SO—, or —SO 2 —;

R 1 and R 2 are independently hydrogen or C 1 -C 4 alkyl;

R 3 is hydrogen or C 1 -C 4 alkyl;

R 4 is hydrogen or —NH 2 ;

one of X 1 , X 2 , X 3 , or X 4 is halogen, —OH, —NH 2 , —NO 2 , —CN, —COOH, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 aminoalkyl, C 1 -C 4 alkylamino, C 2 -C 4 acyl, C 2 -C 4 acylamino, C 1 -C 4 alkylthio, C 1 -C 4 perfluoroalkyl, C 1 -C 4 perfluoroalkyloxy, or C 1 -C 4 alkoxycarbonyl optionally substituted with halogen or C 1 -C 4 alkyl, while the others of X 1 , X 2 , X 3 , or X 4 are independently hydrogen,

provided, however, that when R 4 is hydrogen, one of X 1 , X 2 , X 3 , or X 4 is —NH 2 , an aminoalkyl group or an alkylamino group.

10. The method of claim 9 , wherein the HDAC inhibitor is a compound of the following formula:

11. The method according to claim 9 , wherein the HDAC inhibitor and the PD-1 inhibitor are administered prior, concurrently, subsequently, or combinations thereof, to a treatment of the primary tumor.

12. The method according to claim 11 , wherein the treatment of the primary tumor is one or more of radiation, surgery, chemotherapy, immunotherapy, targeted therapy, hormone therapy, stem cell transplant, cryotherapy, laser therapy, and precision medicine.

13. The method according to claim 9 , wherein before administration of the HDAC inhibitor in combination with the PD-1 inhibitor, the HDAC inhibitor is administered alone for a period of time.

14. The method according to claim 9 , wherein the metastasis that is reduced is metastasis to one or more of the adrenal gland, brain, spinal cord, bone, lung, liver and/or pleura, gastrointestinal tract, peritoneum, muscle, lymph nodes and skin.

15. The method according to claim 9 , wherein the primary tumor is a cancer of the breast, lung, liver, bladder, skin, brain, intestine, colon, kidney, ovary, pancreas, prostate, stomach, thyroid, head and neck, gastroesophageal tract, connective tissue, myeloid cells, lymphatic cells, or uterus.

16. The method according to claim 9 , wherein the primary tumor is advanced metastatic breast cancer.