Simutaneous targeting all Raf isoforms offers the prospect of enhanced efficacy as well as reduced potential for resistance. Described herein is the discovery and characterization of a series of pyrimidine scaffold with DFG-out conformation as potent Pan-Raf inhibitors. Among them, I-41 with excellent Pan-Raf potency demonstrates inhibitory activity against BRaf phenotypic melanoma and BRaf phenotypic colon cells. The western blot results for the Erk inhibition in human melanoma SK-Mel-2 cell lines showed I-41 inhibited the proliferation of SK-Mel-2 cell lines without paradoxical activation of Erk, which supported I-41 may become a good candidate compound to overcome the resistance of melanoma against the current BRaf inhibitor therapy. I-41 also have a favorable pharmacokinetic profile in rat. Synthesis, SAR, lead selection, and evaluation of the key compounds studies are described.
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| http://dx.doi.org/10.1016/j.ejmech.2017.02.041 | DOI Listing |
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