Discovery of a series of dimethoxybenzene FGFR inhibitors with 5pyrrolo2,3-pyrazine scaffold: structure-activity relationship, crystal structural characterization and study.

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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Discovery of a series of dimethoxybenzene FGFR inhibitors with 5pyrrolo2,3-pyrazine scaffold: structure-activity relationship, crystal structural characterization and study.

Author: Peng WEI ¹ ; Bo LIU ² ; Ruifeng WANG ¹ ; Yinglei GAO ² ; Lanlan LI ² ; Yuchi MA ³ ; Zhiwei QIAN ³ ; Yuelei CHEN ³ ; Maosheng CHENG ¹ ; Meiyu GENG ² ; Jingkang SHEN ³ ; Dongmei ZHAO ¹ ; Jing AI ² ; Bing XIONG ³
Author Information

1. Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
2. Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
3. Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Publication Type:Journal Article
Keywords: 5-Hydrosulfonyl-5H-pyrrolo[2,3-b]pyrazine; Crystallography; Fibroblast growth factor; Hybrid; Inhibitor; Selectivity; Structure-based; Tyrosine kinase receptor
From: Acta Pharmaceutica Sinica B 2019;9(2):351-368
CountryChina
Language:English
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 metabolic stability tests and pharmacokinetic profiling, a representative compound () was selected and tested in xenograft mouse model, and the result demonstrated that inhibitor was effective against tumors with FGFR genetic alterations, exhibiting potential for further development.