title: 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).
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.
authors.affiliation: La Jolla Laboratories, Pfizer Worldwide Research and Development, San Diego, California 92121, USA. jean.cui@pfizer.com
authors.forename: J Jean
authors.initials: JJ
authors.lastname: Cui
authors.forename: Michelle
authors.initials: M
authors.lastname: Tran-Dubé
authors.forename: Hong
authors.initials: H
authors.lastname: Shen
authors.forename: Mitchell
authors.initials: M
authors.lastname: Nambu
authors.forename: Pei-Pei
authors.initials: PP
authors.lastname: Kung
authors.forename: Mason
authors.initials: M
authors.lastname: Pairish
authors.forename: Lei
authors.initials: L
authors.lastname: Jia
authors.forename: Jerry
authors.initials: J
authors.lastname: Meng
authors.forename: Lee
authors.initials: L
authors.lastname: Funk
authors.forename: Iriny
authors.initials: I
authors.lastname: Botrous
authors.forename: Michele
authors.initials: M
authors.lastname: McTigue
authors.forename: Neil
authors.initials: N
authors.lastname: Grodsky
authors.forename: Kevin
authors.initials: K
authors.lastname: Ryan
authors.forename: Ellen
authors.initials: E
authors.lastname: Padrique
authors.forename: Gordon
authors.initials: G
authors.lastname: Alton
authors.forename: Sergei
authors.initials: S
authors.lastname: Timofeevski
authors.forename: Shinji
authors.initials: S
authors.lastname: Yamazaki
authors.forename: Qiuhua
authors.initials: Q
authors.lastname: Li
authors.forename: Helen
authors.initials: H
authors.lastname: Zou
authors.forename: James
authors.initials: J
authors.lastname: Christensen
authors.forename: Barbara
authors.initials: B
authors.lastname: Mroczkowski
authors.forename: Steve
authors.initials: S
authors.lastname: Bender
authors.forename: Robert S
authors.initials: RS
authors.lastname: Kania
authors.forename: Martin P
authors.initials: MP
authors.lastname: Edwards
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000077547:Crizotinib; D018360:Crystallography, X-Ray; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D008968:Molecular Conformation; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D007211:Indoles; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases