B-Raf（V600E）的吡唑并吡啶抑制剂。第1部分：选择性、口服生物可利用且有效的抑制剂的研发。
Pyrazolopyridine Inhibitors of B-Raf(V600E). Part 1: The Development of Selective, Orally Bioavailable, and Efficacious Inhibitors.
作者信息
Wenglowsky Steve, Ren Li, Ahrendt Kateri A, Laird Ellen R, Aliagas Ignacio, Alicke Bruno, Buckmelter Alex J, Choo Edna F, Dinkel Victoria, Feng Bainian, Gloor Susan L, Gould Stephen E, Gross Stefan, Gunzner-Toste Janet, Hansen Joshua D, Hatzivassiliou Georgia, Liu Bonnie, Malesky Kim, Mathieu Simon, Newhouse Brad, Raddatz Nicholas J, Ran Yingqing, Rana Sumeet, Randolph Nikole, Risom Tyler, Rudolph Joachim, Savage Scott, Selby LeAnn T, Shrag Michael, Song Kyung, Sturgis Hillary L, Voegtli Walter C, Wen Zhaoyang, Willis Brandon S, Woessner Richard D, Wu Wen-I, Young Wendy B, Grina Jonas
机构信息
Array BioPharma, 3200 Walnut Street, Boulder, Colorado 80301, United States.
Genentech, Inc., 1 DNA Way, South San Francisco, California 94080-4990, United States.
出版信息
ACS Med Chem Lett. 2011 Mar 8;2(5):342-7. doi: 10.1021/ml200025q. eCollection 2011 May 12.
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.
摘要
B-Raf激酶的V600E突变导致丝裂原活化蛋白激酶（MAPK）信号通路的组成性激活，约7%的所有癌症中存在该突变。通过基于结构的设计，开发了一系列新型的B-Raf（V600E）吡唑并吡啶抑制剂。优化后鉴定出3-甲氧基吡唑并吡啶17和19，它们是强效、选择性且口服生物可利用的药物，在由B-Raf（V600E）驱动的小鼠异种移植模型中抑制肿瘤生长，对体重无影响。基于它们的体内疗效和初步安全性概况，选择17和19进行进一步的临床前评估。
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