Biological Activity
b-raf inhibitor 1 is an inhibitor of b-raf kinase with ic50 values of 0.31μm and 0.72μm for cell proliferation, respectively in a375 and hct116 [1].b-raf is important in signal transduction and some mutant b-raf occurs in cancer cells. the most common mutation of these is v600e, which makes b-raf kinase constitutively active. b-raf inhibitor 1 belongs to the type iia inhibitors and binds to the dfg-out atp-binding site of b-raf. the selectivity of b-raf inhibitor 1 is less than of other type inhibitors. besides mutant b-raf, it can also inhibit wild type b-raf and other tyrosine kinase. in cells with wild type b-raf, b-raf inhibitor 1 can activate the raf-mek-erk signaling pathway via raf dimerization. the preclinical toxicity test shows b-raf inhibitor 1 can induce hyperplasia in a mouse model [1, 2].
in vitro
B-Raf inhibitor 1 (Compound 13) inhibits A375 and HCT-116 proliferation with IC 50 s of 0.31 and 0.72 μM, respectively. B-Raf inhibitor 1 (Compound 13) binds to and stabilizes B-Raf in a DFG-out, inactive conformation in which the ATP pocket is partially filled by Phe595 and Gly596 from the DFG motif.
References
[1] wang x, kim j. conformation-specific effects of raf kinase inhibitors. j med chem. 2012 sep 13;55(17):7332-41.
[2] smith al, demorin ff, paras na, huang q, petkus jk, doherty em, nixey t, kim jl, whittington da, epstein lf, lee mr, rose mj, babij c, fernando m, hess k, le q, beltran p, carnahan j. selective inhibitors of the mutant b-raf pathway: discovery of a potent and orally bioavailable aminoisoquinoline. j med chem. 2009 oct 22;52(20):6189-92.
