Original Articles
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. 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[J]. Acta Pharmaceutica Sinica B, 2019, 9(2): 351-368

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
Peng Weia,b, Bo Liuc, Ruifeng Wanga,b, Yinglei Gaoc, Lanlan Lic, Yuchi Mab, Zhiwei Qianb, Yuelei Chenb, Maosheng Chenga, Meiyu Gengc, Jingkang Shenb, Dongmei Zhaoa, Jing Aic, Bing Xiongb
a Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China;
b Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;
c Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Abstract:
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.
Key words:    Fibroblast growth factor    Tyrosine kinase receptor    Structure-based    Crystallography    Selectivity    Hybrid    5-Hydrosulfonyl-5H-pyrrolo[2,3-b]pyrazine    Inhibitor   
Received: 2018-08-15     Revised: 2018-11-09
DOI: 10.1016/j.apsb.2018.12.008
Funds: We are grateful for financial support from the National Natural Science Foundation of China (Grants No.81661148046 and 81773762,China) and 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),and the program for Liaoning Innovative Research Team at Shenyang Pharmaceutical University (China).
Corresponding author: Dongmei Zhao, Jing Ai, Bing Xiong     Email:Zhaodm@syphu.edu.cn;jai@simma.c.cn;bxiong@simm.ac.cn
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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

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