Structure-based optimization of a series of selective BET inhibitors containing aniline or indoline groups
文献类型：期刊论文
| 作者 | Hu, Jianping1,3; Wang, Yingqing2 ; Li, Yanlian3; Cao, Danyan3; Xu, Lin2; Song, ShanShan2; Damaneh, Mohammadali Soleimani1,2; Li, Jian3; Chen, Yuelei3; Wang, Xin3
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| 刊名 | EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 2018-04-25 |
| 卷号 | 150页码:156-175 |
| 关键词 | BRD4 BI2536 Indoline WPF binders c-Myc PD-L1 |
| ISSN号 | 0223-5234 |
| DOI | 10.1016/j.ejmech.2018.02.070 |
| 文献子类 | Article |
| 英文摘要 | Recently, several kinase inhibitors were found to also inhibit bromodomains, providing a new strategy for the discovery of bromodomain inhibitors. Along this line, starting from PLK1-BRD4 dual inhibitor BI-2536, we discovered a new series of dihydroquinoxalin-2(1H)-one with aniline and indoline WPF binders as selective BRD4 inhibitors. They showed better BRD4-BD1 potency and negligible PLK1 kinase activity comparing with BI-2536. Additionally, dihydroquinoxalin-2(1H)-ones containing indoline group showed profound activities in molecular and cellular based assays. Throughout the study, compounds 9,28 and 37 showed significant inhibitory activity for c-Myc or PD-L1 protein expression and mRNA transcription both at concentration of 0.2 and 1 mu M. Compound 9 was found possessing the best balance of binding affinity, in vitro metabolic stability and in vivo pharmacokinetic properties. Therefore, it was selected for in vivo pharmacological study. By using MM.1S cell derived xenograft model, we confirmed compound 9 showed comparable in vivo tumor inhibition to phase II investigation drug I-BET762, which, together with the novel WPF binder, further indicated the utility of this series of BRD4 inhibitors. (C) 2018 Elsevier Masson SAS. All rights reserved. |
| WOS关键词 | HISTONE ACETYLTRANSFERASES ; DRUG DISCOVERY ; BROMODOMAIN ; BRD4 ; 2-THIAZOLIDINONES ; TRANSCRIPTION ; EXPRESSION |
| 资助项目 | National Natural Science Foundation of China[81330076] ; National Science & Technology Major Project "Key New Drug Creation and Manufacturing Program" of China[2014ZX09507-002] ; "Personalized Medicines-Molecular Signature-based Drug Discovery and Development", Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020318] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000430891400013 |
| 出版者 | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/279793]  |
| 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 药物化学研究室 |
| 通讯作者 | Miao, Zehong; Xiong, Bing |
| 作者单位 | 1.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Hu, Jianping,Wang, Yingqing,Li, Yanlian,et al. Structure-based optimization of a series of selective BET inhibitors containing aniline or indoline groups[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2018,150:156-175. |
| APA | Hu, Jianping.,Wang, Yingqing.,Li, Yanlian.,Cao, Danyan.,Xu, Lin.,...&Xiong, Bing.(2018).Structure-based optimization of a series of selective BET inhibitors containing aniline or indoline groups.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,150,156-175. |
| MLA | Hu, Jianping,et al."Structure-based optimization of a series of selective BET inhibitors containing aniline or indoline groups".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 150(2018):156-175. |
入库方式： OAI收割
来源：上海药物研究所
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