Discovery of dihydropyridinone derivative as a covalent EZH2 degrader

被引：2

作者：

Zhou, Bin ^{[1
,2
]}

Wang, Beilei ^{[1
,3
,4
]}

Zou, Fengming ^{[1
,3
,4
]}

Mei, Husheng ^{[1
,2
]}

Liu, Qingwang ^{[1
,3
,4
]}

Qi, Shuang ^{[1
,3
,4
,5
]}

Wang, Wenliang ^{[1
,5
]}

Jin, Rui ^{[1
,3
]}

Wang, Aoli ^{[1
,3
,4
]}

Chen, Yongfei ^{[1
,3
,4
]}

Liu, Feiyang ^{[1
,4
,5
]}

Wang, Wenchao ^{[1
,2
,3
,4
,5
]}

Liu, Jing ^{[1
,2
,3
,4
,5
,6
]}

Liu, Qingsong ^{[1
,2
,3
,4
,5
,6
]}

机构：

[1] Chinese Acad Sci, Inst Hlth & Med Technol, Hefei Inst Phys Sci, Anhui Prov Key Lab Med Phys & Technol, Hefei 230031, Anhui, Peoples R China

[2] Univ Sci & Technol China, Hefei 230026, Anhui, Peoples R China

[3] Chinese Acad Sci, Hefei Canc Hosp, Hefei 230031, Anhui, Peoples R China

[4] Precis Med Res Lab Anhui Prov, Hefei 230088, Anhui, Peoples R China

[5] Primary Cell Engn Joint Lab Anhui Prov, Hefei 230088, Anhui, Peoples R China

[6] Chinese Acad Sci, Hefei Inst Phys Sci, Hefei 230031, Anhui, Peoples R China

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2023年 / 261卷

基金：

中国国家自然科学基金;

关键词：

Enhancer of zeste homolog 2; Covalent inhibitor; EZH2; degrader; HISTONE METHYLTRANSFERASE EZH2; LYSINE; 27; POLYCOMB; INHIBITOR; LYMPHOMA; COMPLEX; DESIGN; HYPERTRIMETHYLATION; IDENTIFICATION; METHYLATION;

D O I：

10.1016/j.ejmech.2023.115825

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

EZH2 is overexpressed in multiple types of cancer and high expression level of EZH2 correlates with poor prognosis. Besides the regulation of H3K27 trimethylation, EZH2 itself regulates its downstream proteins in a PRC2-and methylation-independent way. Starting from an approved EZH2 inhibitor EPZ-6438, we used covalent drug design and medicinal chemistry approaches to discover a novel covalent EZH2 degrader 38, which forms a covalent bond with EZH2 Cys663 and showed strong biochemical activities against EZH2 WT and mutants. Compound 38 exhibited potent antiproliferation effects against both B-cell lymphoma and TNBC cell lines by reducing the levels of H3K27me3 and EZH2. The mass spectrometry, washout and competition experiments confirmed the covalent binding of 38 to EZH2. This study demonstrates that covalent EZH2 degraders could provide an opportunity for the development of promising new drug candidates.

引用

页数：23

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