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Pyrazolopyridine Inhibitors of B-RafV600E. Part 1: The Development of Selective, Orally Bioavailable, and Efficacious Inhibitors

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journal contribution
posted on 12.05.2011 by Steve Wenglowsky, Li Ren, Kateri A. Ahrendt, Ellen R. Laird, Ignacio Aliagas, Bruno Alicke, Alex J. Buckmelter, Edna F. Choo, Victoria Dinkel, Bainian Feng, Susan L. Gloor, Stephen E. Gould, Stefan Gross, Janet Gunzner-Toste, Joshua D. Hansen, Georgia Hatzivassiliou, Bonnie Liu, Kim Malesky, Simon Mathieu, Brad Newhouse, Nicholas J. Raddatz, Yingqing Ran, Sumeet Rana, Nikole Randolph, Tyler Risom, Joachim Rudolph, Scott Savage, LeAnn T. Selby, Michael Shrag, Kyung Song, Hillary L. Sturgis, Walter C. Voegtli, Zhaoyang Wen, Brandon S. Willis, Richard D. Woessner, Wen-I Wu, Wendy B. Young, Jonas Grina
The V600E mutation of B-Raf kinase results in constitutive activation of the MAPK signaling pathway and is present in approximately 7% of all cancers. Using structure-based design, a novel series of pyrazolopyridine inhibitors of B-RafV600E was developed. Optimization led to the identification of 3-methoxy pyrazolopyridines 17 and 19, potent, selective, and orally bioavailable agents that inhibited tumor growth in a mouse xenograft model driven by B-RafV600E with no effect on body weight. On the basis of their in vivo efficacy and preliminary safety profiles, 17 and 19 were selected for further preclinical evaluation.