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

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• 作者：J. Jean Cui ; Michele McTigue ; Mitchell Nambu ; Michelle Tran-Dub茅 ; 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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：September 27, 2012
• 年：2012
• 卷：55
• 期：18
• 页码：8091-8109
• 全文大小：870K
• 年卷期：v.55,no.18(September 27, 2012)
• ISSN：1520-4804

文摘

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.