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
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
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DOI：
10.1016/j.apsb.2018.12.008
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发表时间：
2018-12
期刊：
影响因子：
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通讯作者：
P. Wei;Bo Liu;Ruifeng Wang;Ying-lei Gao;Lanlan Li;Yu-chi Ma;Zhiwei Qian;Yuelei Chen;M. Cheng;M. Geng;Jingkang Shen;Dongmei Zhao;Jing Ai;B. Xiong
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文献类型：
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作者：
P. Wei;Bo Liu;Ruifeng Wang;Ying-lei Gao;Lanlan Li;Yu-chi Ma;Zhiwei Qian;Yuelei Chen;M. Cheng;M. Geng;Jingkang Shen;Dongmei Zhao;Jing Ai;B. Xiong
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 structuresingle bondactivity relationship was elaborated. Together within vitrometabolic stability tests andin vivopharmacokinetic profiling, a representative compound (35) was selected and tested in xenograft mouse model, and the result demonstrated that inhibitor35was effective against tumors with FGFR genetic alterations, exhibiting potential for further development.
