COMBINATION THERAPIES OF HDAC INHIBITORS AND TUBULIN INHIBITORS
Provided herein are combinations that include a histone deacetylase inhibitor and tubulin inhibitor such as eribulin or a pharmaceutically acceptable salt thereof that are useful for treating cancer, including reducing cancer metastasis.
1 - 22 . (canceled)
23 . A method for treating a breast cancer in a subject, comprising administering to said subject a therapeutically effective amount of a compound of formula I:
or a pharmaceutically acceptable salt thereof, in combination with a tubulin inhibitor;
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 , a C 1 -C 4 aminoalkyl group or a C 1 -C 4 alkylamino group.
24 . The method of claim 23 , wherein the tubulin inhibitor is eribulin, paclitaxel, epothilone, docetaxel, discodermolide, colchicine, combrestatin, 2-methoxyestradiol, methoxy benzenesulfonamides (E7010), vinblastine, vincristine, vinorelbine, vinfluine, dolastatins, halichondrins, hemiasterlins, cryptophysin 52, or a pharmaceutically acceptable salt thereof.
25 . The method of claim 23 , wherein the breast cancer is metastatic breast cancer.
26 . A method for treating a breast cancer in a subject, comprising administering to said subject a therapeutically effective amount of a compound of the following formula:
or a pharmaceutically acceptable salt thereof, in combination with a tubulin inhibitor.
27 . The method of claim 26 , wherein the tubulin inhibitor is eribulin, paclitaxel, epothilone, docetaxel, discodermolide, colchicine, combrestatin, 2-methoxyestradiol, methoxy benzenesulfonamides (E7010), vinblastine, vincristine, vinorelbine, vinfluine, dolastatins, halichondrins, hemiasterlins, cryptophysin 52, or a pharmaceutically acceptable salt thereof.
28 . The method of claim 27 , wherein the tubulin inhibitor is eribulin, or a pharmaceutically acceptable salt thereof.
29 . The method of claim 28 , wherein the tubulin inhibitor is eribulin mesylate.
30 . The method of claim 29 , wherein eribulin mesylate is administered intravenously.
31 . The method of claim 30 , wherein eribulin mesylate is administered intravenously at a dose of 1.4 mg/m 2 over 2 to 5 minutes on days 1 and 8 of a 21-day cycle.
32 . The method of claim 26 , wherein the compound is administered orally.
33 . The method of claim 32 , wherein the compound is administered orally at a dose of about 5, 10, 17.5, 25, 30, 32.5, or 50 mg twice per week (BIW) or three times per week (TIW).
34 . The method of claim 26 , wherein the breast cancer is metastatic breast cancer.
35 . The method of claim 26 , wherein the breast cancer is triple negative breast cancer.
36 . The method of claim 26 , wherein said treatment results in one or more of the following: (i) reduction in the number of cancer cells; (ii) reduction in tumor volume; (iii) increase in tumor regression rate; (iv) reduction in or slowing of cancer cell infiltration into peripheral organs; (v) reduction in or slowing of tumor metastasis; (vi) reduction in or inhibition of tumor growth; (vii) prevention or delay of occurrence and/or recurrence of the cancer, and/or extending of disease- or tumor-free survival time; (viii) increase in overall survival time; (ix) reduction in the frequency of treatment; (x) reduction in cancer burden, and (XI) relieving of one or more of symptoms associated with the cancer.
37 . The method of claim 26 , wherein said treatment results in reduction in tumor metastasis.
38 . The method of claim 37 , wherein metastasis to one of more of the adrenal gland, brain, spinal cord, bone, lung, liver, pleura, gastrointestinal tract, peritoneum, muscle, lymph nodes and skin is reduced.
39 . The method of claim 37 , wherein metastasis to lung is reduced.
40 . The method of claim 26 , wherein before administering the compound in combination with the tubulin inhibitor, the compound is administered as a single agent.
41 . The method of claim 26 , further comprising treating the subject with an E-selectin inhibitor, or plerixafor, or a combination of an E-selectin inhibitor and plerixafor.