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 Med Chem. 2011 Sep 22;54(18):6342-63. doi: 10.1021/jm2007613.
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
  • 1. La Jolla Laboratories, Pfizer Worldwide Research and Development, San Diego, California 92121, USA. [email protected]
PMID: 21812414 DOI: 10.1021/jm2007613
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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