Discovery of a New-Generation S-Adenosylmethionine-Noncompetitive Covalent Inhibitor Targeting the Lysine Methyltransferase Enhancer of Zeste Homologue 2
文献类型：期刊论文
| 作者 | Zhang, Yi2; Yang, Hong3,4; Li, Bingbing2; Li, Jiayi1,5; Li, Huaxuan2; Shi, Qiongyu4; Li, Bang2; Wang, Zekun3,5; Zheng, Jiahong2; Zhang, Ying4,5,6 |
| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
 |
| 出版日期 | 2023-05-19 |
| 卷号 | 66期号:11页码:7629-7644 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/acs.jmedchem.3c00504 |
| 通讯作者 | Huang, Xun(xhuang@simm.ac.cn) ; Wang, Yuanxiang(wangyx95@mail.sysu.edu.cn) |
| 英文摘要 | Thefirst-generation enhancer of zeste homologue 2 (EZH2) inhibitorssuffer from several limitations, such as high dosage, cofactor S-adenosylmethionine(SAM) competition, and acquired drug resistance. Development of covalentEZH2 inhibitors that are noncompetitive with cofactor SAM offers anopportunity to overcome these disadvantages. The structure-based designof compound 16 (BBDDL2059) as a highly potent and selectivecovalent inhibitor of EZH2 is presented in this context. 16 inhibits EZH2 enzymatic activity at sub-nanomolar concentrationsand achieves low nanomolar potencies in cell growth inhibition. Thekinetic assay revealed that 16 is noncompetitive withthe cofactor SAM, providing the basis for its superior activity overnoncovalent and positive controls by reducing competition with cofactorSAM and offering a preliminary proof for its covalent inhibition nature.Mass spectrometric analysis and washout experiments firmly establishits covalent inhibition mechanism. This study demonstrates that covalentinhibition of EZH2 can offer a new opportunity for the developmentof promising new-generation drug candidates. |
| WOS关键词 | EZH2 INHIBITOR ; SELECTIVE INHIBITOR ; DESIGN ; PRC2 ; LYMPHOMA ; COMPLEX ; POTENT ; IDENTIFICATION ; METHYLATION |
| 资助项目 | National Natural Science Foundation of China[21977128] ; National Natural Science Foundation of China[21922707] ; National Natural Science Foundation of China[82173835] ; National Natural Science Foundation of China[81991523] ; Guangzhou Basic and Applied Basic Research Foundation[202103000097] ; Collaborative Innovation Cluster Project of Shanghai Municipal Commission of Health and Family Planning[2019CXJQ02] ; Open Program of State Key Laboratory of New Drug Development[SIMM2105KF-04] ; SA-SIBS Scholarship Program ; Shanghai Municipal Science and Technology Major Project |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| 出版者 | AMER CHEMICAL SOC |
| WOS记录号 | WOS:001006034900001 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/306290]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Huang, Xun; Wang, Yuanxiang |
| 作者单位 | 1.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China 2.Sun Yat Sen Univ, Sch Pharmaceut Sci, Balance Based Drug Discovery Lab, Guangzhou 510006, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med SIMM, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China 4.Lingang Lab, Shanghai 200031, Peoples R China 5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 6.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zhang, Yi,Yang, Hong,Li, Bingbing,et al. Discovery of a New-Generation S-Adenosylmethionine-Noncompetitive Covalent Inhibitor Targeting the Lysine Methyltransferase Enhancer of Zeste Homologue 2[J]. JOURNAL OF MEDICINAL CHEMISTRY,2023,66(11):7629-7644. |
| APA | Zhang, Yi.,Yang, Hong.,Li, Bingbing.,Li, Jiayi.,Li, Huaxuan.,...&Wang, Yuanxiang.(2023).Discovery of a New-Generation S-Adenosylmethionine-Noncompetitive Covalent Inhibitor Targeting the Lysine Methyltransferase Enhancer of Zeste Homologue 2.JOURNAL OF MEDICINAL CHEMISTRY,66(11),7629-7644. |
| MLA | Zhang, Yi,et al."Discovery of a New-Generation S-Adenosylmethionine-Noncompetitive Covalent Inhibitor Targeting the Lysine Methyltransferase Enhancer of Zeste Homologue 2".JOURNAL OF MEDICINAL CHEMISTRY 66.11(2023):7629-7644. |
入库方式： OAI收割
来源：上海药物研究所
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