Identifying a non-conserved site for achieving allosteric covalent inhibition of CECR2
文献类型：期刊论文
| 作者 | Tang, Cai-ling6,7; Li, Yuan-qing6,7; Du, Xi-kun5; Fang, Xiao-xia4,7; Guang, Yi-man6; Li, Pei-zhuo6,7; Chen, Shuang4,7; Xue, Sheng-yu6,7; Yu, Jia-min6,7; Liu, Xiao-yi5 |
| 刊名 | ACTA PHARMACOLOGICA SINICA
 |
| 出版日期 | 2025-01-20 |
| 页码 | 16 |
| 关键词 | dynamics simulation CECR2 covalent inhibitor allosteric effect |
| ISSN号 | 1671-4083 |
| DOI | 10.1038/s41401-024-01452-z |
| 英文摘要 | The bromodomain (BRD) represents a highly conserved structural module that provides BRD proteins with fundamental functionality in modulating protein-protein interactions involved in diverse biological processes such as chromatin-mediated gene transcription, DNA recombination, replication and repair. Consequently, dysregulation of BRD proteins has been implicated in the pathogenesis of numerous human diseases. In recent years, considerable scientific endeavors have focused on unraveling the molecular mechanisms underlying BRDs and developing inhibitors that target these domains. While these inhibitors compete for binding with the acetylated lysine binding site of BRDs, achieving inhibition of BRD proteins via competitive pocket binding has proven challenging due to the conserved nature of these pockets. To address this limitation, the present study employed dynamic simulations for a comprehensive analysis, leading to the identification of a non-conserved pocket in CECR2 for achieving BRD family inhibition through allosteric modulation. Subsequently, the compound BAY 11-7085 was proven capable of covalently binding to C494 of this pocket after covalent docking and biological verification in vitro. The allosteric inhibition strategy of CECR2 was further verified by the structurally optimized compound LC-CE-7, which is an allosteric covalent CECR2 inhibitor with anti-cancer effects in MDA-MB-231 cells. |
| WOS关键词 | SULFONYL ACRYLONITRILES ; BIOLOGICAL EVALUATION ; BROMODOMAIN ; DYNAMICS ; DROSOPHILA ; PROTEINS ; DESIGN ; REGION ; GENES ; MODE |
| 资助项目 | National Centre for Protein Science Shanghai (Shanghai Science Research Center, Protein Expression and Purification system) |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001400845700001 |
| 出版者 | NATURE PUBL GROUP |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/315899]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Xiong, Huan; Liang, Zhong-jie; Ding, Hong |
| 作者单位 | 1.Soochow Univ, Jiangsu Prov Engn Res Ctr Precis Diagnost & Therap, Suzhou 215123, Peoples R China 2.Guizhou Med Univ, Sch Pharm, Guiyang 550004, Peoples R China 3.Zunyi Med Univ, Sch Pharm, Zunyi 563000, Peoples R China 4.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Peoples R China 5.Soochow Univ, Suzhou Med Coll, Sch Life Sci, Ctr Syst Biol,Dept Bioinformat, Suzhou 215123, Peoples R China 6.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 7.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China |
| 推荐引用方式 GB/T 7714 | Tang, Cai-ling,Li, Yuan-qing,Du, Xi-kun,et al. Identifying a non-conserved site for achieving allosteric covalent inhibition of CECR2[J]. ACTA PHARMACOLOGICA SINICA,2025:16. |
| APA | Tang, Cai-ling.,Li, Yuan-qing.,Du, Xi-kun.,Fang, Xiao-xia.,Guang, Yi-man.,...&Ding, Hong.(2025).Identifying a non-conserved site for achieving allosteric covalent inhibition of CECR2.ACTA PHARMACOLOGICA SINICA,16. |
| MLA | Tang, Cai-ling,et al."Identifying a non-conserved site for achieving allosteric covalent inhibition of CECR2".ACTA PHARMACOLOGICA SINICA (2025):16. |
入库方式： OAI收割
来源：上海药物研究所
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