Identification and Biological Evaluation of Novel Type II B‐RafV600E 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‐RafV600E. 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‐RafV600E 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‐RafV600E 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.