Discovery and Optimization of a Novel Series of Potent Mutant B-RafV600E Selective Kinase Inhibitors

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• 作者：Melissa M. Vasbinder ; Brian Aquila ; Martin Augustin ; Huawei Chen ; Tony Cheung ; Donald Cook ; Lisa Drew ; Benjamin P. Fauber ; Steve Glossop ; Michael Grondine ; Edward Hennessy ; Jeffrey Johannes ; Stephen Lee ; Paul Lyne ; Mario M枚rtl ; Charles Omer ; Sangeetha Palakurthi ; Timothy Pontz ; Jon Read ; Li Sha ; Minhui Shen ; Stefan Steinbacher ; Haixia Wang ; Allan Wu ; Minwei Ye
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：March 14, 2013
• 年：2013
• 卷：56
• 期：5
• 页码：1996-2015
• 全文大小：775K
• 年卷期：v.56,no.5(March 14, 2013)
• ISSN：1520-4804

文摘

B-Raf represents an attractive target for anticancer therapy and the development of small molecule B-Raf inhibitors has delivered new therapies for metastatic melanoma patients. We have discovered a novel class of small molecules that inhibit mutant B-Raf^V600E kinase activity both in vitro and in vivo. Investigations into the structure鈥揳ctivity relationships of the series are presented along with efforts to improve upon the cellular potency, solubility, and pharmacokinetic profile. Compounds selectively inhibited B-Raf^V600E in vitro and showed preferential antiproliferative activity in mutant B-Raf^V600E cell lines and exhibited selectivity in a kinase panel against other kinases. Examples from this series inhibit growth of a B-Raf^V600E A375 xenograft in vivo at a well-tolerated dose. In addition, aminoquinazolines described herein were shown to display pERK elevation in nonmutant B-Raf cell lines in vitro.