期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 56, 期 10, 页码 3833-3851出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm301793a
关键词
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资金
- Program of Excellent Young Scientist of Chinese Academy of Sciences [KSCX2-EW-Q3-01]
- Interdisciplinary Cooperation Team Program for Science and Technology Innovation of the Chinese Academy of Sciences
- 100 Talents Project of CAS
- The National Natural Science Foundation of China [81072580, 91013010, 21172233]
- National Program on Key Basic Research Project (973 Program) [2009CB940903]
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.
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