| Literature DB >> 24900315 |
Steve Wenglowsky1, Li Ren1, Kateri A Ahrendt1, Ellen R Laird1, Ignacio Aliagas2, Bruno Alicke2, Alex J Buckmelter1, Edna F Choo2, Victoria Dinkel1, Bainian Feng2, Susan L Gloor1, Stephen E Gould2, Stefan Gross1, Janet Gunzner-Toste2, Joshua D Hansen1, Georgia Hatzivassiliou2, Bonnie Liu2, Kim Malesky2, Simon Mathieu2, Brad Newhouse1, Nicholas J Raddatz1, Yingqing Ran2, Sumeet Rana1, Nikole Randolph1, Tyler Risom1, Joachim Rudolph2, Scott Savage2, LeAnn T Selby1, Michael Shrag1, Kyung Song2, Hillary L Sturgis1, Walter C Voegtli1, Zhaoyang Wen2, Brandon S Willis1, Richard D Woessner1, Wen-I Wu1, Wendy B Young2, Jonas Grina1.
Abstract
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-Raf(V600E) 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-Raf(V600E) 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.Entities:
Keywords: B-RafV600E; MAPK pathway; amorphous spray-dried dispersion; pyrazolopyridine; targeted therapy
Year: 2011 PMID： 24900315 PMCID： PMC4017973 DOI： 10.1021/ml200025q
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345