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
收藏
页数：23
相关论文
共 50 条
  • [1] Discovery of a first-in-class EZH2 selective degrader
    Anqi Ma
    Elias Stratikopoulos
    Kwang-Su Park
    Jieli Wei
    Tiphaine C. Martin
    Xiaobao Yang
    Megan Schwarz
    Violetta Leshchenko
    Alexander Rialdi
    Brandon Dale
    Alessandro Lagana
    Ernesto Guccione
    Samir Parekh
    Ramon Parsons
    Jian Jin
    Nature Chemical Biology, 2020, 16 : 214 - 222
  • [2] Discovery of a first-in-class EZH2 selective degrader
    Ma, Anqi
    Stratikopoulos, Elias
    Park, Kwang-Su
    Wei, Jieli
    Martin, Tiphaine C.
    Yang, Xiaobao
    Schwarz, Megan
    Leshchenko, Violetta
    Rialdi, Alexander
    Dale, Brandon
    Lagana, Alessandro
    Guccione, Ernesto
    Parekh, Samir
    Parsons, Ramon
    Jin, Jian
    NATURE CHEMICAL BIOLOGY, 2020, 16 (02) : 214 - +
  • [3] Discovery of a novel, highly potent EZH2 PROTAC degrader for targeting non-canonical oncogenic functions of EZH2
    Velez, Julia
    Dale, Brandon
    Park, Kwang-Su
    Kaniskan, H. Umit
    Yu, Xufen
    Jin, Jian
    EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2024, 267
  • [4] Dissecting and targeting noncanonical functions of EZH2 in multiple myeloma via an EZH2 degrader
    Yu, Xufen
    Wang, Jun
    Gong, Weida
    Ma, Anqi
    Shen, Yudao
    Zhang, Chengwei
    Liu, Xijuan
    Cai, Ling
    Liu, Jing
    Wang, Gang Greg
    Jin, Jian
    ONCOGENE, 2023, 42 (13) : 994 - 1009
  • [5] Dissecting and targeting noncanonical functions of EZH2 in multiple myeloma via an EZH2 degrader
    Xufen Yu
    Jun Wang
    Weida Gong
    Anqi Ma
    Yudao Shen
    Chengwei Zhang
    Xijuan Liu
    Ling Cai
    Jing Liu
    Gang Greg Wang
    Jian Jin
    Oncogene, 2023, 42 : 994 - 1009
  • [6] The discovery of SKLB-0335 as a paralog-selective EZH2 covalent inhibitor
    Zhang, Qiangsheng
    Hu, Xi
    Li, Lu
    Zhang, Lidan
    Wan, Guoquan
    Feng, Qiang
    Zhu, Yongxia
    Wang, Ningyu
    Liu, Zhihao
    Yu, Luoting
    CHEMICAL COMMUNICATIONS, 2021, 57 (24) : 3006 - 3009
  • [7] Discovery of a Novel Covalent EZH2 Inhibitor Based on Tazemetostat Scaffold for the Treatment of Ovarian Cancer
    Zhang, Qiangsheng
    Chen, Xinyi
    Cao, Jiaying
    Yang, Wan
    Wan, Guoquan
    Feng, Qiang
    Zhou, Shuyan
    Yang, Hongling
    Wang, Ningyu
    Liu, Zhihao
    Xiao, Hongtao
    Zhu, Yongxia
    Yu, Luoting
    JOURNAL OF MEDICINAL CHEMISTRY, 2023, 66 (03) : 1725 - 1741
  • [8] Discovery of a Novel Covalent EZH2 Inhibitor Based on Tazemetostat Scaffold for the Treatment of Ovarian Cancer
    Zhang, Qiangsheng
    Chen, Xinyi
    Cao, Jiaying
    Yang, Wan
    Wan, Guoquan
    Feng, Qiang
    Zhou, Shuyan
    Yang, Hongling
    Wang, Ningyu
    Liu, Zhihao
    Xiao, Hongtao
    Zhu, Yongxia
    Yu, Luoting
    JOURNAL OF MEDICINAL CHEMISTRY, 2023, : 1725 - 1741
  • [9] Covalent inhibitors of EZH2: Design, synthesis and evaluation
    Zhang, Qiangsheng
    Chen, Xinyi
    Hu, Xi
    Duan, Xianjie
    Wan, Guoquan
    Li, Lu
    Feng, Qiang
    Zhang, Yiqian
    Wang, Ningyu
    Yu, Luoting
    BIOMEDICINE & PHARMACOTHERAPY, 2022, 147
  • [10] Discovery of a novel, highly potent VHL-recruiting EZH2 PROTAC degrader targeting MLL-r AML
    Velez, Julia
    Yu, Xufen
    Dale, Brandon
    Park, Kwang-Su
    Kaniskan, H. Umit
    Jin, Jian
    MOLECULAR CANCER THERAPEUTICS, 2023, 22 (12)
12345