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
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DOI：
10.1021/jm300967g
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发表时间：
2012-09-27
影响因子：
7.3
通讯作者：
Christensen, James
中科院分区：
文献类型：
--
作者：
Cui, J. Jean;McTigue, Michele;Christensen, James
c-MET受体酪氨酸激酶是一个有吸引力的肿瘤学靶点，因为它在人类肿瘤发生和肿瘤进展中起关键作用。在c-MET HTS活动期间鉴定了羟吲哚酰肼命中6，随后证明其对广泛的其他激酶具有不寻常的选择性程度。相关羟吲哚酰肼c-MET抑制剂10与非磷酸化c-MET激酶结构域的共晶结构揭示了与精致选择性特征相关的独特结合模式。使用基于结构的药物设计，用化学和代谢稳定的三唑并吡嗪支架替换化学不稳定的羟吲哚酰肼支架。药物化学先导优化产生了2-（4-（1-（喹啉-6-基甲基）-1H-[1，2，3]三唑并[4，5-B]吡嗪-6-基）-1H-吡唑-1-基）乙醇（2，PF-04217903），这是一种极其强效和精密选择性的c-MET抑制剂。2在c-MET依赖性肿瘤模型中表现出有效的肿瘤生长抑制作用，具有良好的口服PK特性和临床前研究中可接受的安全性特征。2例进展至I期肿瘤学背景下的临床评价。
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.