NMR-based platform for fragment-based lead discovery used in screening BRD4-targeted compounds
文献类型：期刊论文
| 作者 | Yu, Jun-lan2,3; Chen, Tian-tian1; Zhou, Chen2,3; Lian, Fu-lin2,3; Tang, Xu-long2,3; Wen, Yi2,3; Shen, Jing-kang4; Xu, Ye-chun1 ; Xiong, Bing4; Zhang, Nai-xia2,3
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| 刊名 | ACTA PHARMACOLOGICA SINICA
 |
| 出版日期 | 2016-07 |
| 卷号 | 37期号:7页码:984-993 |
| 关键词 | fragment-based lead discovery NMR bromodomain BRD4 inhibitors |
| ISSN号 | 1671-4083 |
| DOI | 10.1038/aps.2016.19 |
| 文献子类 | Article |
| 英文摘要 | Aim: Fragment-based lead discovery (FBLD) is a complementary approach in drug research and development. In this study, we established an NMR-based FBLD platform that was used to screen novel scaffolds targeting human bromodomain of BRD4, and investigated the binding interactions between hit compounds and the target protein. Methods: 1D NMR techniques were primarily used to generate the fragment library and to screen compounds. The inhibitory activity of hits on the first bromodomain of BRD4 [BRD4(I)] was examined using fluorescence anisotropy binding assay. 2D NMR and X-ray crystallography were applied to characterize the binding interactions between hit compounds and the target protein. Results: An NMR-based fragment library containing 539 compounds was established, which were clustered into 56 groups (8-10 compounds in each group). Eight hits with new scaffolds were found to inhibit BRD4(I). Four out of the 8 hits (compounds 1, 2, 8 and 9) had IC50 values of 100-260 mu mol/L, demonstrating their potential for further BRD4-targeted hit-to-lead optimization. Analysis of the binding interactions revealed that compounds 1 and 2 shared a common quinazolin core structure and bound to BRD4(I) in a non-acetylated lysine mimetic mode. Conclusion: An NMR-based platform for FBLD was established and used in discovery of BRD4-targeted compounds. Four potential hit-to-lead optimization candidates have been found, two of them bound to BRD4(I) in a non-acetylated lysine mimetic mode, being selective BRD4(I) inhibitors. |
| WOS关键词 | BET BROMODOMAIN INHIBITORS ; CHEMICAL-SHIFT INDEX ; DRUG DISCOVERY ; DNA METHYLATION ; SELECTIVE-INHIBITION ; TERMINAL DOMAIN ; EPIGENETICS ; BINDING ; CANCER ; POTENT |
| 资助项目 | National Natural Science Foundation of China[21272246] ; National Natural Science Foundation of China[31300608] ; National Natural Science Foundation of China[81330076] ; National Key Basic Research Program of China[2013CB910900] |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| CSCD记录号 | CSCD:5743045 |
| WOS记录号 | WOS:000379430900013 |
| 出版者 | ACTA PHARMACOLOGICA SINICA |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/275971]  |
| 专题 | 药物化学研究室 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 分析化学研究室 |
| 通讯作者 | Xiong, Bing; Zhang, Nai-xia |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Analyt Chem, Shanghai 201203, Peoples R China; 3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China; 4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Yu, Jun-lan,Chen, Tian-tian,Zhou, Chen,et al. NMR-based platform for fragment-based lead discovery used in screening BRD4-targeted compounds[J]. ACTA PHARMACOLOGICA SINICA,2016,37(7):984-993. |
| APA | Yu, Jun-lan.,Chen, Tian-tian.,Zhou, Chen.,Lian, Fu-lin.,Tang, Xu-long.,...&Zhang, Nai-xia.(2016).NMR-based platform for fragment-based lead discovery used in screening BRD4-targeted compounds.ACTA PHARMACOLOGICA SINICA,37(7),984-993. |
| MLA | Yu, Jun-lan,et al."NMR-based platform for fragment-based lead discovery used in screening BRD4-targeted compounds".ACTA PHARMACOLOGICA SINICA 37.7(2016):984-993. |
入库方式： OAI收割
来源：上海药物研究所
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