2. Academic Validation
  3. 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

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

  • J Med Chem. 2012 Sep 27;55(18):8091-109. doi: 10.1021/jm300967g.
J Jean Cui 1,  Michele McTigue,  Mitchell Nambu,  Michelle Tran-Dubé,  Mason Pairish,  Hong Shen,  Lei Jia,  Hengmiao Cheng,  Jacqui Hoffman,  Phuong Le,  Mehran Jalaie,  Gilles H Goetz,  Kevin Ryan,  Neil Grodsky,  Ya-li Deng,  Max Parker,  Sergei Timofeevski,  Brion W Murray,  Shinji Yamazaki,  Shirley Aguirre,  Qiuhua Li,  Helen Zou,  James Christensen
Affiliations

Affiliation

  • 1 La Jolla Laboratories, Pfizer Worldwide Research and Development, 10770 Science Center Drive, San Diego, California 92121, USA. jean.cui@pfizer.com
PMID: 22924734 DOI: 10.1021/jm300967g
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.

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