1399857-74-9Relevant articles and documents
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)-1 H -[1,2,3]triazolo[4,5- b ]pyrazin-6-yl)-1 H -pyrazol-1-yl)ethanol (PF-04217903) for the treatment of cancer
Cui, J. Jean,McTigue, Michele,Nambu, Mitchell,Tran-Dube, Michelle,Pairish, Mason,Shen, Hong,Jia, Lei,Cheng, Hengmiao,Hoffman, Jacqui,Le, Phuong,Jalaie, Mehran,Goetz, Gilles H.,Ryan, Kevin,Grodsky, Neil,Deng, Ya-Li,Parker, Max,Timofeevski, Sergei,Murray, Brion W.,Yamazaki, Shinji,Aguirre, Shirley,Li, Qiuhua,Zou, Helen,Christensen, James
, p. 8091 - 8109,19 (2020/09/15)
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.
