[CAS NO. 1195768-06-9]  Dabrafenib Mesylate

Dabrafenib displayed compelling inhibitory activity in enzyme and cellular mechanistic assays, and in cell proliferation assays in B-Raf-driven melanoma lines, SKMEL28 and A375P F11 (IC50 = 3 and 8 nM, respectively), and colorectal carcinoma line Colo205 (IC50 = 7 nM). Dabrafenib has a minimal effect in vitro on cells with wild-type B-Raf (HFF IC50 = 3.0 μM) and in tumor cells not harboring the activating B-Raf mutation. It is highly selective, exhibiting >500-fold selectivity for B-Raf compared to most kinases screened. Significant activity (<100-fold selectivity) was observed for a single kinase in the panel, Alk5. GSK2118436 is significantly less effective at inhibiting SMAD2/3 phosphorylation (IC50 = 3.7 μM) compared with inhibiting ERK phosphorylation (IC50 = 4 nM) in a cellular context. Cellular inhibition of BRAF kinase activity by dabrafenib resulted in decreased MEK and ERK phosphorylation and inhibition of cell proliferation through an initial G1 cell cycle arrest, followed by cell death.