Discovery of Potent Irreversible Pan-Fibroblast Growth Factor Receptor (FGFR) Inhibitors,Journal of Medicinal Chemistry

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Discovery of Potent Irreversible Pan-Fibroblast Growth Factor Receptor (FGFR) Inhibitors
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-03-09 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01843
Yuming Wang _{1,

2} , Lijun Li _{2,

3} , Jun Fan _{1,

2} , Yang Dai _{2,

3} , Alan Jiang _{2,

3} , Meiyu Geng _{2,

3} , Jing Ai _{2,

3} , Wenhu Duan _{1,

2}

Affiliation

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, 9g displayed clear antitumor activities in NCI-H1581 and SNU-16 xenograft mice models. Additionally, the diluting method confirmed the irreversible binding of 9g to FGFR.

中文翻译：

强大的不可逆泛成纤维细胞生长因子受体（FGFR）抑制剂的发现

成纤维细胞生长因子受体（FGFR1-4）是许多癌症中有希望的治疗靶标。随着人们对不可逆抑制剂的兴趣重新兴起，人们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，这些抑制剂可以共价靶向FGFR P环中保守的半胱氨酸。在本文中，我们使用了一种结构指导的方法，该方法通过计算机辅助模拟进行了合理化处理，从而发现了新型且不可逆的pan-FGFR抑制剂9g，该抑制剂比VEGFR2（血管内皮生长因子）具有更好的FGFR体外活性和良好的选择性。受体2）。在体内研究中，9g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9g与FGFR不可逆结合。

更新日期：2018-03-09

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