Design, synthesis and biological evaluation of tetrahydronaphthyridine derivatives as bioavailable CDK4/6 inhibitors for cancer therapy

doi:10.1016/j.ejmech.2018.02.022

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	Design, synthesis and biological evaluation of tetrahydronaphthyridine derivatives as bioavailable CDK4/6 inhibitors for cancer therapy
	Zha, Chuantao 1; Deng, Wenjia 2,3; Fu, Yan 1; Tang, Shuai 2; Lan, Xiaojing2 ; Ye, Yan 1; Su, Yi 2; Jiang, Lei 1; Chen, Yi2 ; Huang, Ying 1
刊名	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
	2018-03-25
卷号	148 页码:140-153
关键词	Structure-based drug design Selective CDK4/6 inhibitors Structure-activity relationship study In vivo antitumor activity
ISSN号	0223-5234
DOI	10.1016/j.ejmech.2018.02.022
文献子类	Article
英文摘要	CDK4/6 pathway is an attractive chemotherapeutic target for antitumor drug discovery and development. Herein, we reported the structure-based design and synthesis of a series of novel tetrahydronaphthyridine analogues as selective CDK4/6 inhibitors. Compound 5 was identified as a hit and then systematically structure optimization study was conducted. These efforts led to compound 28, which exhibited excellent in vitro potencies against CDK4/6 enzymatic activity with high selectivity over CDK1, and against Colo-205 cell growth. The compound demonstrated favorable in vitro metabolic and robust mice pharmacokinetic properties. In Colo-205 xenograft models, compound 28 showed potent tumor growth inhibition with acceptable toxic effects, which could serve as a novel anticancer agent for further preclinical study. (C) 2018 Elsevier Masson SAS. All rights reserved.
资助项目	China International Science and Technology Cooperation Program[2015DFM30040] ; National Science and Technology Major Project[2015ZX09101009]
WOS关键词	METASTATIC BREAST-CANCER ; CELL-CYCLE ; PERSPECTIVES ; COMBINATION ; GEMCITABINE ; PATHWAYS ; TARGETS ; DRUGS
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
WOS记录号	WOS:000428824700012
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279841]
专题	药理学第一研究室中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Huang, Min; Wan, Huixin
作者单位	1.Shanghai HaiHe Pharmaceut Co Ltd, Pudong New Area, 421 Newton Rd,Zhangjiang Hitech Pk, Shanghai 201203, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Medica, Div Antitumor Pharmacol, State Key Lab Drug Res,Pudong New Area, 555 Zuchongzhi Rd,Zhangjiang Hitech Pk, Shanghai 201203, Peoples R China; 3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
推荐引用方式 GB/T 7714	Zha, Chuantao,Deng, Wenjia,Fu, Yan,et al. Design, synthesis and biological evaluation of tetrahydronaphthyridine derivatives as bioavailable CDK4/6 inhibitors for cancer therapy[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2018,148:140-153.
APA	Zha, Chuantao.,Deng, Wenjia.,Fu, Yan.,Tang, Shuai.,Lan, Xiaojing.,...&Wan, Huixin.(2018).Design, synthesis and biological evaluation of tetrahydronaphthyridine derivatives as bioavailable CDK4/6 inhibitors for cancer therapy.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,148,140-153.
MLA	Zha, Chuantao,et al."Design, synthesis and biological evaluation of tetrahydronaphthyridine derivatives as bioavailable CDK4/6 inhibitors for cancer therapy".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 148(2018):140-153.