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. 2011 Sep 22;54(18):6342-63.
doi: 10.1021/jm2007613. Epub 2011 Aug 18.

Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK)

J Jean Cui  1 , Michelle Tran-Dubé, 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
Affiliations

Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK)

J Jean Cui et al. J Med Chem. .

Abstract

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.

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