Pyrazolylamine Derivatives Reveal the Conformational Switching between Type I and Type II Binding Modes of Anaplastic Lymphoma Kinase (ALK)

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• 作者：Chih-Hsiang Tu ; Wen-Hsing Lin ; Yi-Hui Peng ; Tsu Hsu ; Jian-Sung Wu ; Chun-Yu Chang ; Cheng-Tai Lu ; Ping-Chiang Lyu ; Chuan Shih ; Weir-Torn Jiaang ; Su-Ying Wu
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：April 28, 2016
• 年：2016
• 卷：59
• 期：8
• 页码：3906-3919
• 全文大小：910K
• 年卷期：0
• ISSN：1520-4804

文摘

Most anaplastic lymphoma kinase (ALK) inhibitors adopt a type I binding mode, but only limited type II ALK structural studies are available. Herein, we present the structure of ALK in complex with N1-(3-4-[([5-(tert-butyl)-3-isoxazolyl]aminocarbonyl)amino]-3-methylphenyl-1H-5-pyrazolyl)-4-[(4-methylpiperazino)methyl]benzamide (5a), a novel ALK inhibitor adopting a type II binding mode. It revealed binding of 5a resulted in the conformational change and reposition of the activation loop, αC-helix, and juxtamembrane domain, which are all important domains for the autoinhibition mechanism and downstream signal pathway regulation of ALK. A structure–activity relationship study revealed that modifications to the structure of 5a led to significant differences in the ALK potency and altered the protein structure of ALK. To the best of our knowledge, this is the first structural biology study to directly observe how changes in the structure of a small molecule can regulate the switch between the type I and type II binding modes and induce dramatic conformational changes.