title: Discovery of a novel class of exquisitely selective mesenchymal-epithelial transition factor (c-MET) protein kinase inhibitors and identification of the clinical candidate 2-(4-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)-1H-pyrazol-1-yl)ethanol (PF-04217903) for the treatment of cancer.
abstract: The c-MET receptor tyrosine kinase is an attractive oncology target because of its critical role in human oncogenesis and tumor progression. An oxindole hydrazide hit 6 was identified during a c-MET HTS campaign and subsequently demonstrated to have an unusual degree of selectivity against a broad array of other kinases. The cocrystal structure of the related oxindole hydrazide c-MET inhibitor 10 with a nonphosphorylated c-MET kinase domain revealed a unique binding mode associated with the exquisite selectivity profile. The chemically labile oxindole hydrazide scaffold was replaced with a chemically and metabolically stable triazolopyrazine scaffold using structure based drug design. Medicinal chemistry lead optimization produced 2-(4-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)-1H-pyrazol-1-yl)ethanol (2, PF-04217903), an extremely potent and exquisitely selective c-MET inhibitor. 2 demonstrated effective tumor growth inhibition in c-MET dependent tumor models with good oral PK properties and an acceptable safety profile in preclinical studies. 2 progressed to clinical evaluation in a Phase I oncology setting.
authors.affiliation: La Jolla Laboratories, Pfizer Worldwide Research and Development, 10770 Science Center Drive, San Diego, California 92121, USA. jean.cui@pfizer.com
authors.forename: J Jean
authors.initials: JJ
authors.lastname: Cui
authors.forename: Michele
authors.initials: M
authors.lastname: McTigue
authors.forename: Mitchell
authors.initials: M
authors.lastname: Nambu
authors.forename: Michelle
authors.initials: M
authors.lastname: Tran-Dubé
authors.forename: Mason
authors.initials: M
authors.lastname: Pairish
authors.forename: Hong
authors.initials: H
authors.lastname: Shen
authors.forename: Lei
authors.initials: L
authors.lastname: Jia
authors.forename: Hengmiao
authors.initials: H
authors.lastname: Cheng
authors.forename: Jacqui
authors.initials: J
authors.lastname: Hoffman
authors.forename: Phuong
authors.initials: P
authors.lastname: Le
authors.forename: Mehran
authors.initials: M
authors.lastname: Jalaie
authors.forename: Gilles H
authors.initials: GH
authors.lastname: Goetz
authors.forename: Kevin
authors.initials: K
authors.lastname: Ryan
authors.forename: Neil
authors.initials: N
authors.lastname: Grodsky
authors.forename: Ya-li
authors.initials: YL
authors.lastname: Deng
authors.forename: Max
authors.initials: M
authors.lastname: Parker
authors.forename: Sergei
authors.initials: S
authors.lastname: Timofeevski
authors.forename: Brion W
authors.initials: BW
authors.lastname: Murray
authors.forename: Shinji
authors.initials: S
authors.lastname: Yamazaki
authors.forename: Shirley
authors.initials: S
authors.lastname: Aguirre
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
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D055808:Drug Discovery; D004355:Drug Stability; D057166:High-Throughput Screening Assays; D006801:Humans; D007211:Indoles / Q000737:chemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D000078183:Oxindoles; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011719:Pyrazines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013379:Substrate Specificity; D014230:Triazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C558663:2-(4-(3-quinolin-6-ylmethyl-3H-(1,2,3)triazolo(4,5-b)pyrazin-5-yl)pyrazol-1-yl)ethanol; D000970:Antineoplastic Agents; D007211:Indoles; D000078183:Oxindoles; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D014230:Triazoles; C022960:2-oxindole; D019859:Proto-Oncogene Proteins c-met