发现苯胺嘧啶作为c-Met和VEGFR-2的双重抑制剂：合成、构效关系及细胞活性
Discovery of Anilinopyrimidines as Dual Inhibitors of c-Met and VEGFR-2: Synthesis, SAR, and Cellular Activity.
作者信息
Zhan Zhengsheng, Ai Jing, Liu Qiufeng, Ji Yinchun, Chen Tiantian, Xu Yechun, Geng Meiyu, Duan Wenhu
机构信息
Department of Medicinal Chemistry, Division of Antitumor Pharmacology, and Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zu Chong Zhi Road, Shanghai 201203, China.
出版信息
ACS Med Chem Lett. 2014 Mar 26;5(6):673-8. doi: 10.1021/ml500066m. eCollection 2014 Jun 12.
Abstract
Both c-Met and VEGFR-2 are important targets for cancer therapies. Here we report a series of potent dual c-Met and VEGFR-2 inhibitors bearing an anilinopyrimidine scaffold. Two novel synthetic protocols were employed for rapid analoguing of the designed molecules for structure-activity relationship (SAR) exploration. Some analogues displayed nanomolar potency against c-Met and VEGFR-2 at enzymatic level. Privileged compounds 3a, 3b, 3g, 3h, and 18a exhibited potent antiproliferative effect against c-Met addictive cell lines with IC50 values ranged from 0.33 to 1.7 μM. In addition, a cocrystal structure of c-Met in complex with 3h has been determined, which reveals the binding mode of c-Met to its inhibitor and helps to interpret the SAR of the analogues.
摘要
c-Met和VEGFR-2都是癌症治疗的重要靶点。在此，我们报道了一系列带有苯胺嘧啶支架的强效双c-Met和VEGFR-2抑制剂。采用了两种新颖的合成方案来快速模拟设计分子以探索构效关系（SAR）。一些类似物在酶水平上对c-Met和VEGFR-2显示出纳摩尔级别的活性。优势化合物3a、3b、3g、3h和18a对c-Met成瘾性细胞系表现出强效的抗增殖作用，IC50值范围为0.33至1.7μM。此外，还确定了c-Met与3h的共晶体结构，该结构揭示了c-Met与其抑制剂的结合模式，并有助于解释类似物的构效关系。
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