成纤维细胞生长因子受体
化学
体内
成纤维细胞生长因子受体1
激酶
对接(动物)
癌症研究
受体
成纤维细胞生长因子
生物化学
药理学
生物
医学
生物技术
护理部
作者
Shihe Hu,Yao-Bin Liu,Jiye Ma,Weijie Ding,Chen Hua,Haifang Jiang,Hongxing Chen,Song Wei,Yao-Bin Liu,Qiaomei Jin,Haoliang Yuan,Libo Yan
标识
DOI:10.1021/acs.jmedchem.3c00455
摘要
Aberrant activation of fibroblast growth factor receptors (FGFRs) has been identified as an oncogenic driver force for multiple cancer types, making FGFRs a compelling target for anticancer therapy. Because of the renewed interest in irreversible inhibitors, considerable efforts have been made to find irreversible FGFR inhibitors. Herein, we discovered a series of novel quinolone-based covalent pan-FGFR inhibitors by further optimizing the lead compound (lenvatinib) under the guidance of molecular docking. The representative pan-FGFR inhibitor I-5 exhibited significant inhibitory potency against FGFR1-4 with nanomolar activity and effectively suppressed the proliferation of Huh-7 and Hep3B HCC cells. I-5 displayed high selectivity against a panel of 369 kinases at 1 μM. The irreversible binding to target proteins was characterized by liquid chromatography and tandem mass spectrometry (LC-MS/MS). Moreover, I-5 exhibited favorable PK properties in vivo and induced significant TGI in the Huh-7 and NCI-H1581 xenograft mouse models.
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