Discovery of a series of dimethoxybenzene FGFR inhibitors with 5H-pyrrolo[2,3-b]pyrazine scaffold: structure–activity relationship, crystal structural characterization and in vivo study

论文摘要

Genomic alterations are commonly found in the signaling pathways of fibroblast growth factor receptors（FGFRs）. Although there is no selective FGFR inhibitors in market, several promising inhibitors have been investigated in clinical trials, and showed encouraging efficacies in patients. By designing a hybrid between the FGFR-selectivity-enhancing motif dimethoxybenzene group and our previously identified novel scaffold, we discovered a new series of potent FGFR inhibitors, with the best one showing sub-nanomolar enzymatic activity. After several round of optimization and with the solved crystal structure, detailed structure–activity relationship was elaborated. Together with in vitro metabolic stability tests and in vivo pharmacokinetic profiling, a representative compound（35） was selected and tested in xenograft mouse model, and the result demonstrated that inhibitor 35 was effective against tumors with FGFR genetic alterations, exhibiting potential for further development.

论文目录

文章来源

类型: 期刊论文

作者: Peng Wei,Bo Liu,Ruifeng Wang,Yinglei Gao,Lanlan Li,Yuchi Ma,Zhiwei Qian,Yuelei Chen,Maosheng Cheng,Meiyu Geng,Jingkang Shen,Dongmei Zhao,Jing Ai,Bing Xiong

来源: Acta Pharmaceutica Sinica B 2019年02期

年度: 2019

分类: 医药卫生科技,工程科技Ⅰ辑

专业: 有机化工,药学

单位: Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University,Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences,Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences

基金: financial support from the National Natural Science Foundation of China(Grants No.81661148046 and81773762,China),the “Personalized Medicines—Molecular Signature-based Drug Discovery and Development”,Strategic Priority Research Program of the Chinese Academy of Sciences(Grants No.XDA12020317,China),the program for Innovative Research Team of the Ministry of Education(China),the program for Liaoning Innovative Research Team at Shenyang Pharmaceutical University(China)

分类号: R94

页码: 351-368

总页数: 18

文件大小: 1925K

下载量: 28

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