Design, synthesis and biological evaluation of tetrahydronaphthyridine derivatives as bioavailable CDK4/6 inhibitors for cancer therapy | |
Zha, Chuantao1; Deng, Wenjia2,3; Fu, Yan1; Tang, Shuai2; Lan, Xiaojing2; Ye, Yan1; Su, Yi2; Jiang, Lei1; Chen, Yi2; Huang, Ying1 | |
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. |
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