The RAS/RAF signaling pathway is an important mediator of tumor cell proliferation and angiogenesis. Among them, B-RAF is the most frequently mutated protein kinase in human cancers. SB-590885 is a selective Raf kinase inhibitor with Kiapp value of 0.16nM for B-Raf (measured by kinase activity), 11-fold greater selectivity over c-Raf (Kiapp=1.72nM), with little inhibition to other human kinases. Treatment with SB-590885, 2μM for 1h, inhibited ERK phosphorylation in Colo205 and HT29 cell lines, as well as potently and preferentially inhibited ERK phosphorylation and proliferation in tumor cells expressing B-RafV600E. Prolonged exposure to SB-590885, at dose ranging 0.1-10μM for 72h, inhibited cellular transformation and proliferation in three-dimensional culture. Daily administration of SB-590885 at dose of 50m/kg, i.p., decreased tumorigenesis in murine xenografts established from mutant B-Raf-expressing A375P melanoma cells[1].
作用机制
SB-590885 occupies the ATP-binding pocket of B-Raf and stabilizes the oncogenic B-Raf kinase domain in an active configuration.[1]
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