Identification and Biological Evaluation of Novel Type II B-Raf^V600E Inhibitors

The mitogen-activated protein kinase (MAPK) pathway plays a vital role in signal transduction networks. Severe diseases may be triggered if it is disturbed by mutated components, especially the kinase B-Raf^V600E . New inhibitors of the kinase are needed as cases of relapse and resistance with the known drugs have been widely reported in the clinic. In the present work, a new class of B-Raf^V600E inhibitors was identified by fragment linking. In vitro and in vivo assays were used to demonstrate the pharmacological properties of the compounds. 3-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}-N-[1-(4-methoxyphenyl)-1H-pyrazol-4-yl]benzamide was the most potent agent with IC₅₀ values of 0.035±0.004 μm (B-Raf^V600E kinase) and 0.39±0.04 μm (A375 cells). Furthermore, no obvious toxicity was observed. Collectively, the results favored justified the design rationale and hinted that this new chemotype might be worth studying further to develop novel B-Raf inhibitor candidates.