Imidazo[4,5-b]pyridine inhibitors of B-Raf kinase |
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| Authors: | Bradley J Newhouse Steve Wenglowsky Jonas Grina Ellen R Laird Walter C Voegtli Li Ren Kateri Ahrendt Alex Buckmelter Susan L Gloor Nathalie Klopfenstein Joachim Rudolph Zhaoyang Wen Xianfeng Li Bainian Feng |
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| Institution: | 1. Array BioPharma Inc., 3200 Walnut Street, Boulder, CO 80301, USA;2. Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA |
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| Abstract: | This Letter details the synthesis and evaluation of imidazo4,5-b]pyridines as inhibitors of B-Raf kinase. These compounds bind in a DFG-in, αC-helix out conformation of B-Raf, which is a binding mode associated with significant kinase selectivity. Structure–activity relationship studies involved optimization of the ATP-cleft binding region of these molecules, and led to compound 23, an inhibitor with excellent enzyme/cell potency, and kinase selectivity. |
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| Keywords: | B-Raf Imidazopyridine Scaffold hopping DFG-in αC-helix out |
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