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| Fragment-Based Drug Discovery of 2-Thiazolidinones as Inhibitors of the Histone Reader BRD4 Bromodomain | |
| Zhao, Lele; Cao, Danyan; Chen, Tiantian; Wang, Yingqing; Miao, Zehong; Xu, Yechun; Chen, Wuyan; Wang, Xin; Li, Yardian; Du, Zhiyan; Xiong, Bing; Li, Jian; Xu, Chunyan（徐春艳）; Zhang, Naixia; He, Jianhua（何建华）; Shen, Jingkang | |
| 2013 | |
| Source Publication | JOURNAL OF MEDICINAL CHEMISTRY
 |
| ISSN | 0022-2623 |
| Volume | 56Issue:10Pages:CONCATENATE(Sheet1!I134,-Sheet1!J134) |
| Abstract | Recognizing acetyllysine of histone is a vital process of epigenetic regulation that is mediated by a protein module called bromodomain. To contribute novel scaffolds for developing into bromodomain inhibitors, we utilize a fragment-based drug discovery approach. By successively applying docking and X-ray crystallography, we were able to identify 9 fragment hits from diffracting more than 60 crystals. In the present work, we described four of them and carried out the integrated lead optimization for fragment 8, which bears a 2-thiazolidinone core. After several rounds of structure guided modifications, we assessed the druggability of 2-thiazolidinone by modulating in vitro pharmacokinetic studies and cellular activity assay. The results showed that two potent compounds of 2-thiazolidinones have good metabolic stability. Also, the cellular assay confirmed the activities of 2-thiazolidinones. Together, we hope the identified 2-thiazolidinone chemotype and other fragment hits described herein can stimulate researchers to develop more diversified bromodomain inhibitors. |
| Indexed By | SCI |
| Language | 英语 |
| Funding Project | 应物所项目组 |
| WOS ID | WOS:000319650100006 |
| Citation statistics | |
| Document Type | 期刊论文 |
| Identifier | http://ir.sinap.ac.cn/handle/331007/13757 |
| Collection | 中科院上海应用物理研究所2011-2020年 |
| Recommended Citation GB/T 7714 | Zhao, Lele,Cao, Danyan,Chen, Tiantian,et al. Fragment-Based Drug Discovery of 2-Thiazolidinones as Inhibitors of the Histone Reader BRD4 Bromodomain[J]. JOURNAL OF MEDICINAL CHEMISTRY,2013,56(10):CONCATENATE(Sheet1!I134,-Sheet1!J134). |
| APA | Zhao, Lele.,Cao, Danyan.,Chen, Tiantian.,Wang, Yingqing.,Miao, Zehong.,...&Shen, Jingkang.(2013).Fragment-Based Drug Discovery of 2-Thiazolidinones as Inhibitors of the Histone Reader BRD4 Bromodomain.JOURNAL OF MEDICINAL CHEMISTRY,56(10),CONCATENATE(Sheet1!I134,-Sheet1!J134). |
| MLA | Zhao, Lele,et al."Fragment-Based Drug Discovery of 2-Thiazolidinones as Inhibitors of the Histone Reader BRD4 Bromodomain".JOURNAL OF MEDICINAL CHEMISTRY 56.10(2013):CONCATENATE(Sheet1!I134,-Sheet1!J134). |
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| Fragment-Based Drug （2024KB） | 开放获取 | CC BY-NC-SA | View Download | |||
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