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赖氨酸特异性去甲基化酶1(LSD1)抑制剂的研究进展

张晓梦, 付金洋, 何雅楠, 弓建红, 杜锟, 吴亚, 支燕乐

张晓梦,付金洋,何雅楠,等. 赖氨酸特异性去甲基化酶1(LSD1)抑制剂的研究进展[J]. 中国药科大学学报,2024,55(5):685 − 696. DOI: 10.11665/j.issn.1000-5048.2023100701
引用本文: 张晓梦,付金洋,何雅楠,等. 赖氨酸特异性去甲基化酶1(LSD1)抑制剂的研究进展[J]. 中国药科大学学报,2024,55(5):685 − 696. DOI: 10.11665/j.issn.1000-5048.2023100701
ZHANG Xiaomeng, FU Jinyang, HE Yanan, et al. Research progress of lysine specific demethylase 1 (LSD1) inhibitors[J]. J China Pharm Univ, 2024, 55(5): 685 − 696. DOI: 10.11665/j.issn.1000-5048.2023100701
Citation: ZHANG Xiaomeng, FU Jinyang, HE Yanan, et al. Research progress of lysine specific demethylase 1 (LSD1) inhibitors[J]. J China Pharm Univ, 2024, 55(5): 685 − 696. DOI: 10.11665/j.issn.1000-5048.2023100701

赖氨酸特异性去甲基化酶1(LSD1)抑制剂的研究进展

基金项目: 国家自然科学基金项目(No.82003566)
详细信息
    通讯作者:

    吴亚: Tel:13783569267 E-mail:wuya0723@126.com

    支燕乐: Tel:13783696291 E-mail:zhiy_l@163.com

  • 中图分类号: R914.2

Research progress of lysine specific demethylase 1 (LSD1) inhibitors

Funds: This study was supported by the National Natural Science Foundation of China (No.82003566)
  • 摘要:

    赖氨酸特异性去甲基化酶1(LSD1)是一种黄素腺嘌呤二核苷酸(FAD)依赖的单胺氧化酶。研究证实,LSD1的异常表达与肿瘤的转移和增殖密切相关,是目前肿瘤靶向治疗的重要靶点之一。另外,LSD1还参与神经退行性疾病、心血管疾病、炎症反应等多种疾病的发生发展。目前,已经有多个抑制剂进入临床研究阶段。本文对LSD1的结构、作用机制以及LSD1抑制剂的研究进展作简要介绍,为设计开发新型LSD1抑制剂提供参考。

    Abstract:

    Lysine specific demethylase1 (LSD1) is a flavin adenine dinucleotide (FAD)-dependent monoamine oxidase. Studies have confirmed that aberrant expression of LSD1 is closely related to tumor metastasis and proliferation, and is currently one of the important targets for tumor-targeted therapy. In addition, LSD1 is involved in the development of various conditions such as neurodegenerative diseases, cardiovascular diseases, and inflammatory responses. Currently, several inhibitors have been developed for the clinical research stage. In this paper, the structure and mechanism of action of LSD1 and the research progress of LSD1 inhibitors are briefly introduced to provide some reference for the design and development of novel LSD1 inhibitors.

  • 图  1   LSD1/CoREST复合物的晶体结构(PDB:2UXN)

    A: LSD1/CoREST复合物的整体结构;B: SWIRM结构域与AOD结构域接触的界面;C: FAD结合区中重要的氨基酸;D: 组蛋白H3(1-7)与LSD1的作用模式

    图  2   LSD1特异性去甲基化作用机制

    图  3   Lys661与FAD形成氢键相互作用

    图  4   TCP与LSD1的作用模式(PDB:2UXX)

    A: LSD1与TCP形成不同加合物的机制;B: TCP-FAD加合物与3个疏水口袋的空腔图

    图  5   基于TCP结构修饰的化合物

    图  6   进入临床的不可逆LSD1抑制剂

    图  7   进入临床的可逆LSD1抑制剂

    图  8   化合物9、化合物10的结构以及化合物10与LSD1的结合模式

    A: 化合物9、化合物10的结构;B: 化合物10(绿色)与LSD1(PDB:2DW4)的分子对接图

    图  9   化合物11的结构及其与LSD1的结合模式

    A: 化合物11的结构;B: 化合物11(绿色)与LSD1(PDB:5X60)的作用模式

    图  10   化合物12及其与LSD1的结合模式

    A: 化合物12的结构;B: 化合物12(绿色)与LSD1(PDB:2V1D)的分子对接图

    图  11   “Y”型构象化合物的结构以及CC-90011与LSD1的结合模式

    A: “Y”型构象的化合物的结构;B: CC-90011(绿色)与LSD1的结合模式图(PDB:6W4K)

    图  12   “Y”型化合物的构效关系

    图  13   化合物16和化合物17的结构及其与LSD1的结合模式

    A: 化合物16和化合物17的结构;B: 化合物16(绿色)与LSD1的结合模式(PDB:5L3E);C: 化合物17(绿色)与LSD1的结合模式(PDB:6TUY)

    图  14   化合物19及其与LSD1的结合模式

    A: 化合物18结构修饰为化合物19;B: 化合物19(绿色)与LSD1的结合模式(PDB:6TE1)

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出版历程
  • 收稿日期:  2023-10-06
  • 刊出日期:  2024-10-24

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