%0 Journal Article
%T Discovery of a series of dimethoxybenzene FGFR inhibitors with 5H-pyrrolo[2,3-b]pyrazine scaffold: structure¨Cactivity relationship, crystal structural characterization and in vivo study
%A Bo Liu
%A Dongmei Zhao
%A Jing Ai
%A Jingkang Shen
%A Lanlan Li
%A Maosheng Cheng
%A Meiyu Geng
%A Peng Wei
%A Ruifeng Wang
%A Yinglei Gao
%A Yuchi Ma
%A Yuelei Chen
%A Zhiwei Qian
%J Archive of "Acta Pharmaceutica Sinica. B".
%D 2019
%R 10.1016/j.apsb.2018.12.008
%X 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¡ªactivity 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
%K Fibroblast growth factor
%K Tyrosine kinase receptor
%K Structure-based
%K Crystallography
%K Selectivity
%K Hybrid
%K 5-Hydrosulfonyl-5H-pyrrolo[2
%K 3-b]pyrazine
%K Inhibitor
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6437634/