Structure Based Drug Design of Crizotinib (PF-02341066), a Potent and Selective Dual Inhibitor of Mesenchymal鈥揈pithelial Transition Factor (c-MET) Kinase and Anaplastic Lymphoma Kinase (ALK)

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• 作者：J. Jean Cui ; Michelle Tran-Dube虂 ; Hong Shen ; Mitchell Nambu ; Pei-Pei Kung ; Mason Pairish ; Lei Jia ; Jerry Meng ; Lee Funk ; Iriny Botrous ; Michele McTigue ; Neil Grodsky ; Kevin Ryan ; Ellen Padrique ; Gordon Alton ; Sergei Timofeevski ; Shinji Yamazaki ; Qiuhua Li ; Helen Zou ; James Christensen ; Barbara Mroczkowski ; Steve Bender ; Robert S. Kania ; Martin P. Edwards
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：September 22, 2011
• 年：2011
• 卷：54
• 期：18
• 页码：6342-6363
• 全文大小：1550K
• 年卷期：v.54,no.18(September 22, 2011)
• ISSN：1520-4804

文摘

Because of the critical roles of aberrant signaling in cancer, both c-MET and ALK receptor tyrosine kinases are attractive oncology targets for therapeutic intervention. The cocrystal structure of 3 (PHA-665752), bound to c-MET kinase domain, revealed a novel ATP site environment, which served as the target to guide parallel, multiattribute drug design. A novel 2-amino-5-aryl-3-benzyloxypyridine series was created to more effectively make the key interactions achieved with 3. In the novel series, the 2-aminopyridine core allowed a 3-benzyloxy group to reach into the same pocket as the 2,6-dichlorophenyl group of 3 via a more direct vector and thus with a better ligand efficiency (LE). Further optimization of the lead series generated the clinical candidate crizotinib (PF-02341066), which demonstrated potent in vitro and in vivo c-MET kinase and ALK inhibition, effective tumor growth inhibition, and good pharmaceutical properties.