Compounds for treatment of cancer
The present invention relates to pharmaceutical compositions for treating cancer comprising BRAF inhibitors, (e.g. vemurafenib) and/or MEK inhibitor, (e.g. trametinib, RO5068760), in combination with anti-tubulin compounds of the invention or other known tubulin inhibitors, and using such compositions for treating cancer such as melanoma, drug-resistant cancer, and cancer metastasis.
1. A method of treating, suppressing, reducing the severity, reducing the risk, or inhibiting BRAF mutant cancer in a subject, comprising administering a composition comprising at least one of a BRAF inhibitor or a MEK inhibitor, in combination with a compound represented by the structure of formula II:
wherein
A is single or fused aromatic or heteroaromatic ring system;
R 1 is H, C 1 -C 6 linear or branched alkyl, aryl, phenyl, benzyl, haloalkyl, aminoalkyl, —OCH 2 Ph, SO 2 -aryl, SO 2 -phenyl, —(C═O)-aryl, —(C═O)-phenyl or OH;
R 4 and R 5 are each independently hydrogen, C 1 -C 6 linear or branched alkyl, C 1 -C 6 linear or branched haloalkyl, C 1 -C 6 linear or branched alkoxy, C 1 -C 6 linear or branched haloalkoxy, F, Cl, Br, I, CF 3 , CN, —CH 2 CN, NH 2 , OH, —OC(O)CF 3 , alkylamino, aminoalkyl, —OCH 2 Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH 2 or NO 2 ; and
n is an integer between 1-4;
or its pharmaceutically acceptable salt, N-oxide, hydrate, tautomer or isomer and a pharmaceutically acceptable carrier.
2. The method of claim 1 wherein said compound of formula II is:
or pharmaceutically acceptable salts thereof or combination thereof.
3. The method of claim 1 , wherein said BRAF inhibitor is vemurafenib, dabrafenib or combination thereof, and said MEK inhibitor is trametinib or RO5068760, or combination thereof.
4. The method according to claim 1 , wherein the BRAF mutant cancer is BRAF inhibitor resistant cancer, melanoma, drug resistant melanoma, or taxane resistant cancer.
5. The method according to claim 4 , wherein said taxane is docetaxel.
6. The method according to claim 1 , wherein the MEK inhibitor is trametinib, selumetinib, RO5068760, MEK162, PD-325901, cobimetinib, CI-1040 or any combination thereof.
7. The method of claim 1 , wherein the cancer is melanoma, thyroid cancer, colorectal cancer, breast cancer, colon cancer, biliary tract cancer, non-small cell lung cancer (NSCLC), or ovarian cancer.
8. The method according to claim 1 , wherein the cancer is melanoma, thyroid cancer, colorectal cancer, or ovarian cancer.
9. The method according to claim 1 , wherein the cancer is melanoma.
10. The method according to claim 9 , wherein the melanoma is drug resistant melanoma.
11. The method according to claim 9 , wherein the melanoma is V600E positive melanoma.