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

文献类型：期刊论文

作者Wei, Peng1,2; Liu, Bo3; Wang, Ruifeng1,2; Gao, Yinglei3; Li, Lanlan; Ma, Yuchi2; Qian, Zhiwei2; Chen, Yuelei2; Cheng, Maosheng1; Geng, Meiyu3
刊名ACTA PHARMACEUTICA SINICA B
出版日期2019-03-01
卷号9期号:2页码:351-368
关键词Fibroblast growth factor Tyrosine kinase receptor Structure-based Crystallography Selectivity Hybrid 5-Hydrosulfonyl-5H- pyrrolo[2.3-b]pyrazine Inhibitor
ISSN号2211-3835
DOI10.1016/j.apsb.2018.12.008
通讯作者Zhao, Dongmei(Zhaodm@syphu.edu.cn) ; Ai, Jing(jai@simma.c.cn) ; Xiong, Bing(bxiong@simm.ac.cn)
英文摘要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. (C) 2019 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.
WOS关键词TARGETED THERAPIES ; CANCER ; ABERRATIONS ; CHALLENGES ; PONATINIB ; AZD4547 ; COMPLEX ; FAMILY ; MODEL
资助项目National Natural Science Foundation of China (China)[81661148046] ; National Natural Science Foundation of China (China)[81773762] ; Personalized Medicines Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences (China)[XDA12020317] ; program for Innovative Research Team of the Ministry of Education (China) ; program for Liaoning Innovative Research Team at Shenyang Pharmaceutical University (China)
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000461052500011
出版者INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES
源URL[http://119.78.100.183/handle/2S10ELR8/290373]  
专题新药研究国家重点实验室
通讯作者Zhao, Dongmei; Ai, Jing; Xiong, Bing
作者单位1.Shenyang Pharmaceut Univ, Key Lab Struct Based Drug Design & Discovery, Minist Educ, Shenyang 110016, Liaoning, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai 201203, Peoples R China
3.Chinese Acad Sci, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Wei, Peng,Liu, Bo,Wang, Ruifeng,et al. Discovery of a series of dimethoxybenzene FGFR inhibitors with 5H-pyrrolo[2,3-b]pyrazine scaffold: structure-activity relationship, crystal structural characterization and and in vivo study[J]. ACTA PHARMACEUTICA SINICA B,2019,9(2):351-368.
APA Wei, Peng.,Liu, Bo.,Wang, Ruifeng.,Gao, Yinglei.,Li, Lanlan.,...&Xiong, Bing.(2019).Discovery of a series of dimethoxybenzene FGFR inhibitors with 5H-pyrrolo[2,3-b]pyrazine scaffold: structure-activity relationship, crystal structural characterization and and in vivo study.ACTA PHARMACEUTICA SINICA B,9(2),351-368.
MLA Wei, Peng,et al."Discovery of a series of dimethoxybenzene FGFR inhibitors with 5H-pyrrolo[2,3-b]pyrazine scaffold: structure-activity relationship, crystal structural characterization and and in vivo study".ACTA PHARMACEUTICA SINICA B 9.2(2019):351-368.

入库方式： OAI收割

来源：上海药物研究所

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