Highly potent and selective 3-N-methylquinazoline-4(3H)-one based inhibitors of B-Raf^V600E kinase

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• 作者：Steve Wenglowsky^a ; Li Ren^a ; ^{li.ren@arraybiopharma.com" class="auth_mail} ; Jonas Grina^a ; Joshua D. Hansen^a ; Ellen R. Laird^a ; David Moreno^a ; Victoria Dinkel^a ; Susan L. Gloor^a ; Gregg Hastings^a ; Sumeet Rana^a ; Kevin Rasor^a ; Hillary L. Sturgis^a ; Walter C. Voegtli^a ; Guy Vigers^a ; Brandon Willis^a ; Simon Mathieu^b ; Joachim Rudolph^b
• 关键词：B-Raf inhibitors ; Type IIB inhibitor ; Kinase drug discovery ; Melonoma
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：15 April, 2014
• 年：2014
• 卷：24
• 期：8
• 页码：1923-1927
• 全文大小：1914 K

文摘

Herein we describe the design of a novel series of ATP competitive B-Raf inhibitors via structure-based methods. These 3-N-methylquinazoline-4(3H)-one based inhibitors exhibit both excellent cellular potency and striking B-Raf selectivity. Optimization led to the identification of compound 16, a potent, selective and orally available agent with excellent pharmacokinetic properties and robust tumor growth inhibition in xenograft studies. Our work also demonstrates that by replacing an aryl amide with an aryl sulfonamide, a multikinase inhibitor such as AZ-628, can be converted to a selective B-Raf inhibitor, a finding that should have broad application in kinase drug discovery.