Potent and selective pyrazole-based inhibitors of B-Raf kinase

Herein we describe a novel pyrazole-based class of ATP competitive B-Raf inhibitors. These inhibitors exhibit both excellent cellular potency and striking B-Raf selectivity. A subset of these inhibitors has demonstrated the ability to inhibit downstream ERK phosphorylation in LOX tumors from mouse xenograft studies.

Graphical abstractWe report herein a series of substituted pyrazoles as inhibitors of B-Raf kinase. Through structure–activity relationship studies, cellular potency, pharmacokinetics, and kinase selectivity were optimized to afford GDC-0879 (10), a compound with good preclinical in vivo activity against tumor xenograft models.Figure optionsDownload full-size imageDownload as PowerPoint slide