discoveryofaseriesofdimethoxybenzenefgfrinhibitorswith5hpyrrolo23bpyrazinescaffoldstructureactivityrelationshipcrystalstructuralcharacterizationandinvivostudy

doi:10.1016/j.apsb.2018.12.008

	discoveryofaseriesofdimethoxybenzenefgfrinhibitorswith5hpyrrolo23bpyrazinescaffoldstructureactivityrelationshipcrystalstructuralcharacterizationandinvivostudy
	Wei Peng 1; Liu Bo 2; Wang Ruifeng 1; Gao Yinglei 2; Li Lanlan 2; Ma Yuchi 2; Qian Zhiwei 2; Chen Yuelei 2; Cheng Maosheng 1; Geng Meiyu 2
刊名	actapharmaceuticasinicab
	2019
卷号	9 期号:2 页码:351
关键词	Fibroblast growth factor Tyrosine kinase receptor Structure-based Crystallography Selectivity Hybrid 5-Hydrosulfonyl-5Hpyrrolo 2 3-bpyrazine Inhibitor
ISSN号	2211-3835
DOI	10.1016/j.apsb.2018.12.008
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.
语种	英语
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/284493]
专题	中国科学院上海药物研究所
作者单位	1.沈阳药科大学 2.中国科学院上海药物研究所
推荐引用方式 GB/T 7714	Wei Peng,Liu Bo,Wang Ruifeng,et al. discoveryofaseriesofdimethoxybenzenefgfrinhibitorswith5hpyrrolo23bpyrazinescaffoldstructureactivityrelationshipcrystalstructuralcharacterizationandinvivostudy[J]. actapharmaceuticasinicab,2019,9(2):351.
APA	Wei Peng.,Liu Bo.,Wang Ruifeng.,Gao Yinglei.,Li Lanlan.,...&Xiong Bing.(2019).discoveryofaseriesofdimethoxybenzenefgfrinhibitorswith5hpyrrolo23bpyrazinescaffoldstructureactivityrelationshipcrystalstructuralcharacterizationandinvivostudy.actapharmaceuticasinicab,9(2),351.
MLA	Wei Peng,et al."discoveryofaseriesofdimethoxybenzenefgfrinhibitorswith5hpyrrolo23bpyrazinescaffoldstructureactivityrelationshipcrystalstructuralcharacterizationandinvivostudy".actapharmaceuticasinicab 9.2(2019):351.