Discovery of Potent Irreversible Pan-Fibroblast Growth Factor Receptor (FGFR) Inhibitors
Discovery of Potent Irreversible Pan-Fibroblast Growth Factor Receptor (FGFR) Inhibitors
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强效不可逆泛成纤维细胞生长因子受体 (FGFR) 抑制剂的发现
DOI：
10.1021/acs.jmedchem.7b01843
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发表时间：
2018
影响因子：
7.3
通讯作者：
Duan Wenhu
中科院分区：
文献类型：
--
作者：
Wang Yuming;Li Lijun;Fan Jun;Dai Yang;Jiang Alan;Geng Meiyu;Ai Jing;Duan Wenhu
成纤维细胞生长因子受体（FGFR 1 -4）是许多癌症中有希望的治疗靶点。随着对不可逆抑制剂的兴趣的重新兴起，已经致力于发现不可逆FGFR抑制剂。目前，正在临床试验中评估几种选择性不可逆抑制剂，其可以共价靶向FGFR的P环中的保守半胱氨酸。在这篇文章中，我们使用了一种结构导向的方法，通过计算机辅助模拟来合理化，以发现新的和不可逆的泛FGFR抑制剂，9 g，它提供了上级FGFR在体外活动和体面的选择性超过VEGFR 2（血管内皮生长因子受体2）。在体内研究中，9 g在NCI-H1581和SNU-16异种移植小鼠模型中显示出明显的抗肿瘤活性。此外，稀释方法证实了9 g与FGFR的不可逆结合。
Fibroblast growth factor receptors (FGFR1–4) are promising therapeutic targets in many cancers. With the resurgence of interest in irreversible inhibitors, efforts have been directed to the discovery of irreversible FGFR inhibitors. Currently, several selective irreversible inhibitors are being evaluated in clinical trials that could covalently target a conserved cysteine in the P-loop of FGFR. In this article, we used a structure-guided approach that is rationalized by a computer-aided simulation to discover the novel and irreversible pan-FGFR inhibitor,9g, which provided superior FGFR in vitro activities and decent selectivity over VEGFR2 (vascular endothelia growth factor receptor 2). In in vivo studies,9gdisplayed clear antitumor activities in NCI-H1581 and SNU-16 xenograft mice models. Additionally, the diluting method confirmed the irreversible binding of9gto FGFR.