• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

用于癌症治疗的小分子MDM2/X抑制剂和PROTAC降解剂：进展与展望

Small-molecule MDM2/X inhibitors and PROTAC degraders for cancer therapy: advances and perspectives.

作者信息

Fang Yuan, Liao Guochao, Yu Bin

机构信息

Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, China.

School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.

出版信息

Acta Pharm Sin B. 2020 Jul;10(7):1253-1278. doi: 10.1016/j.apsb.2020.01.003. Epub 2020 Jan 14.

DOI:10.1016/j.apsb.2020.01.003
PMID:32874827
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7452049/
Abstract

Blocking the MDM2/X-P53 protein-protein interaction has been widely recognized as an attractive therapeutic strategy for the treatment of cancers. Numerous small-molecule MDM2 inhibitors have been reported since the release of the structure of the MDM2-P53 interaction in 1996, SAR405838, NVP-CGM097, MK-8242, RG7112, RG7388, DS-3032b, and AMG232 currently undergo clinical evaluation for cancer therapy. This review is intended to provide a comprehensive and updated overview of MDM2 inhibitors and proteolysis targeting chimera (PROTAC) degraders with a particular focus on how these inhibitors or degraders are identified from starting points, strategies employed, structure-activity relationship (SAR) studies, binding modes or co-crystal structures, biochemical data, mechanistic studies, and preclinical/clinical studies. Moreover, we briefly discuss the challenges of designing MDM2/X inhibitors for cancer therapy such as dual MDM2/X inhibition, acquired resistance and toxicity of P53 activation as well as future directions.

摘要

阻断MDM2/X-P53蛋白-蛋白相互作用已被广泛认为是一种有吸引力的癌症治疗策略。自1996年MDM2-P53相互作用结构公布以来，已报道了许多小分子MDM2抑制剂，SAR405838、NVP-CGM097、MK-8242、RG7112、RG7388、DS-3032b和AMG232目前正在进行癌症治疗的临床评估。本综述旨在全面、更新地概述MDM2抑制剂和靶向嵌合体（PROTAC）降解剂，特别关注这些抑制剂或降解剂如何从起始点被识别、所采用的策略、构效关系（SAR）研究、结合模式或共晶体结构、生化数据、机制研究以及临床前/临床研究。此外，我们简要讨论了设计用于癌症治疗的MDM2/X抑制剂所面临的挑战，如双重MDM2/X抑制、P53激活的获得性耐药和毒性以及未来方向。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b70a/7452049/213417f09e31/gr26.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b70a/7452049/e226a93f7f83/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b70a/7452049/ee02c7db61c1/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b70a/7452049/0d78a46199e9/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b70a/7452049/cbce01534d6a/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b70a/7452049/c72e24a5f024/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b70a/7452049/eb738138f3d0/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b70a/7452049/dc9bd920e523/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b70a/7452049/37fa5fd0d823/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b70a/7452049/8eb7c7e51983/gr8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b70a/7452049/ed4b15f7aa58/gr9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b70a/7452049/f2458573c95c/gr10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b70a/7452049/a7a3d492267f/gr11.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b70a/7452049/cac35344587f/gr12.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b70a/7452049/76dc44f764dc/gr13.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b70a/7452049/bf8daf801237/gr14.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b70a/7452049/4b47572dc024/gr15.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b70a/7452049/b83839ed341e/gr16.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b70a/7452049/5d1472637987/gr17.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b70a/7452049/03c4a17efa21/gr18.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b70a/7452049/e47c4418e5e1/gr19.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b70a/7452049/fb2dd9fa3403/gr20.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b70a/7452049/4d7b05012be5/gr21.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b70a/7452049/80f497973a54/gr22.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b70a/7452049/eb2aa925d6bf/gr23.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b70a/7452049/75ca6eda483b/gr24.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b70a/7452049/c624f8eabd16/gr25.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b70a/7452049/213417f09e31/gr26.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b70a/7452049/e226a93f7f83/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b70a/7452049/ee02c7db61c1/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b70a/7452049/0d78a46199e9/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b70a/7452049/cbce01534d6a/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b70a/7452049/c72e24a5f024/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b70a/7452049/eb738138f3d0/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b70a/7452049/dc9bd920e523/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b70a/7452049/37fa5fd0d823/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b70a/7452049/8eb7c7e51983/gr8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b70a/7452049/ed4b15f7aa58/gr9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b70a/7452049/f2458573c95c/gr10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b70a/7452049/a7a3d492267f/gr11.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b70a/7452049/cac35344587f/gr12.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b70a/7452049/76dc44f764dc/gr13.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b70a/7452049/bf8daf801237/gr14.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b70a/7452049/4b47572dc024/gr15.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b70a/7452049/b83839ed341e/gr16.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b70a/7452049/5d1472637987/gr17.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b70a/7452049/03c4a17efa21/gr18.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b70a/7452049/e47c4418e5e1/gr19.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b70a/7452049/fb2dd9fa3403/gr20.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b70a/7452049/4d7b05012be5/gr21.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b70a/7452049/80f497973a54/gr22.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b70a/7452049/eb2aa925d6bf/gr23.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b70a/7452049/75ca6eda483b/gr24.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b70a/7452049/c624f8eabd16/gr25.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b70a/7452049/213417f09e31/gr26.jpg

相似文献

1
Small-molecule MDM2/X inhibitors and PROTAC degraders for cancer therapy: advances and perspectives.用于癌症治疗的小分子MDM2/X抑制剂和PROTAC降解剂：进展与展望
Acta Pharm Sin B. 2020 Jul;10(7):1253-1278. doi: 10.1016/j.apsb.2020.01.003. Epub 2020 Jan 14.
2
The development of piperidinones as potent MDM2-P53 protein-protein interaction inhibitors for cancer therapy.哌啶酮类作为有效的 MDM2-P53 蛋白-蛋白相互作用抑制剂在癌症治疗中的发展。
Eur J Med Chem. 2018 Nov 5;159:1-9. doi: 10.1016/j.ejmech.2018.09.044. Epub 2018 Sep 18.
3
PROTAC Degraders with Ligands Recruiting MDM2 E3 Ubiquitin Ligase: An Updated Perspective.通过招募MDM2 E3泛素连接酶的配体构建的PROTAC降解剂：最新观点
Acta Mater Med. 2022;1(2):244-259. doi: 10.15212/amm-2022-0010. Epub 2022 May 31.
4
MDM2 inhibition: an important step forward in cancer therapy.MDM2 抑制：癌症治疗的重要一步。
Leukemia. 2020 Nov;34(11):2858-2874. doi: 10.1038/s41375-020-0949-z. Epub 2020 Jul 10.
5
The HDM2 (MDM2) Inhibitor NVP-CGM097 Inhibits Tumor Cell Proliferation and Shows Additive Effects with 5-Fluorouracil on the p53-p21-Rb-E2F1 Cascade in the p53wild type Neuroendocrine Tumor Cell Line GOT1.HDM2（MDM2）抑制剂 NVP-CGM097 抑制肿瘤细胞增殖，并与 5-氟尿嘧啶在 p53 野生型神经内分泌肿瘤细胞系 GOT1 中对 p53-p21-Rb-E2F1 级联反应表现出相加作用。
Neuroendocrinology. 2018;106(1):1-19. doi: 10.1159/000453369. Epub 2016 Nov 21.
6
Potent effect of the MDM2 inhibitor AMG232 on suppression of glioblastoma stem cells.MDM2 抑制剂 AMG232 对神经胶质瘤干细胞抑制的强烈作用。
Cell Death Dis. 2018 Jul 18;9(8):792. doi: 10.1038/s41419-018-0825-1.
7
Simple Structural Modifications Converting a Bona fide MDM2 PROTAC Degrader into a Molecular Glue Molecule: A Cautionary Tale in the Design of PROTAC Degraders.简单结构修饰将真正的 MDM2 PROTAC 降解剂转化为分子胶：PROTAC 降解剂设计中的一个警示故事。
J Med Chem. 2019 Nov 14;62(21):9471-9487. doi: 10.1021/acs.jmedchem.9b00846. Epub 2019 Oct 21.
8
MDM2 small-molecule antagonist RG7112 activates p53 signaling and regresses human tumors in preclinical cancer models.MDM2 小分子拮抗剂 RG7112 激活 p53 信号通路并在临床前癌症模型中使人类肿瘤消退。
Cancer Res. 2013 Apr 15;73(8):2587-97. doi: 10.1158/0008-5472.CAN-12-2807. Epub 2013 Feb 11.
9
MDM2 Inhibitors for Cancer Therapy: The Past, Present, and Future.MDM2 抑制剂在癌症治疗中的应用：过去、现在与未来。
Pharmacol Rev. 2024 May 2;76(3):414-453. doi: 10.1124/pharmrev.123.001026.
10
MDM2 antagonists as a novel treatment option for acute myeloid leukemia: perspectives on the therapeutic potential of idasanutlin (RG7388).MDM2拮抗剂作为急性髓系白血病的一种新型治疗选择：关于idasanutlin（RG7388）治疗潜力的观点
Onco Targets Ther. 2019 Apr 16;12:2903-2910. doi: 10.2147/OTT.S172315. eCollection 2019.

引用本文的文献

1
Cytotoxic and proapoptotic effects of alizarin in mice with Ehrlich solid tumor: novel insights into ERα-mediated MDM2/p-Rb/E2F1 signaling pathway.茜草素对艾氏实体瘤小鼠的细胞毒性和促凋亡作用：对雌激素受体α介导的MDM2/p-视网膜母细胞瘤蛋白/E2F1信号通路的新见解
Naunyn Schmiedebergs Arch Pharmacol. 2025 Jun 28. doi: 10.1007/s00210-025-04196-7.
2
Research Progress of PROTAC-Degraded CDKs in the Treatment of Breast Cancer.PROTAC 降解的细胞周期蛋白依赖性激酶在乳腺癌治疗中的研究进展
Breast Cancer (Dove Med Press). 2025 Jun 13;17:511-521. doi: 10.2147/BCTT.S527906. eCollection 2025.
3
Ferroptosis as a therapeutic vulnerability in MDM2 inhibition in dedifferentiated liposarcoma.

本文引用的文献

1
Degradation of proteins by PROTACs and other strategies.通过PROTACs和其他策略进行蛋白质降解
Acta Pharm Sin B. 2020 Feb;10(2):207-238. doi: 10.1016/j.apsb.2019.08.001. Epub 2019 Aug 13.
2
Simple Structural Modifications Converting a Bona fide MDM2 PROTAC Degrader into a Molecular Glue Molecule: A Cautionary Tale in the Design of PROTAC Degraders.简单结构修饰将真正的 MDM2 PROTAC 降解剂转化为分子胶：PROTAC 降解剂设计中的一个警示故事。
J Med Chem. 2019 Nov 14;62(21):9471-9487. doi: 10.1021/acs.jmedchem.9b00846. Epub 2019 Oct 21.
3
Development of selective small molecule MDM2 degraders based on nutlin.
铁死亡作为去分化脂肪肉瘤中MDM2抑制的治疗弱点。
Oncol Lett. 2025 Apr 7;29(6):269. doi: 10.3892/ol.2025.15015. eCollection 2025 Jun.
4
Targeting MDM2-p53 interaction for breast cancer therapy.靶向MDM2-p53相互作用用于乳腺癌治疗。
Oncol Res. 2025 Mar 19;33(4):851-861. doi: 10.32604/or.2025.058956. eCollection 2025.
5
Designer polyQ fusion proteins sequester USP7/HDM2 for modulating P53 functionality.设计的多聚谷氨酰胺融合蛋白隔离USP7/HDM2以调节P53功能。
iScience. 2025 Feb 13;28(3):112025. doi: 10.1016/j.isci.2025.112025. eCollection 2025 Mar 21.
6
Structure and function of MDM2 and MDM4 in health and disease.MDM2和MDM4在健康与疾病中的结构与功能
Biochem J. 2025 Feb 17;482(4):BCJ20240757. doi: 10.1042/BCJ20240757.
7
A pH-responsive PROTAC-based nanosystem triggers tumor-specific ferroptosis to construct in situ tumor vaccines.一种基于pH响应性PROTAC的纳米系统触发肿瘤特异性铁死亡以构建原位肿瘤疫苗。
Mater Today Bio. 2025 Jan 24;31:101523. doi: 10.1016/j.mtbio.2025.101523. eCollection 2025 Apr.
8
Unraveling the Guardian: p53's Multifaceted Role in the DNA Damage Response and Tumor Treatment Strategies.解读守护者：p53在DNA损伤应答及肿瘤治疗策略中的多面角色
Int J Mol Sci. 2024 Dec 1;25(23):12928. doi: 10.3390/ijms252312928.
9
From regulation to deregulation of p53 in hematologic malignancies: implications for diagnosis, prognosis and therapy.从血液系统恶性肿瘤中p53的调控到去调控：对诊断、预后和治疗的影响
Biomark Res. 2024 Nov 14;12(1):137. doi: 10.1186/s40364-024-00676-9.
10
Insights into the Interaction Mechanisms of Peptide and Non-Peptide Inhibitors with MDM2 Using Gaussian-Accelerated Molecular Dynamics Simulations and Deep Learning.基于高斯加速分子动力学模拟和深度学习的肽类和非肽类抑制剂与 MDM2 相互作用机制的研究。
Molecules. 2024 Jul 18;29(14):3377. doi: 10.3390/molecules29143377.
基于 nutlin 的选择性小分子 MDM2 降解剂的开发。
Eur J Med Chem. 2019 Aug 15;176:476-491. doi: 10.1016/j.ejmech.2019.05.046. Epub 2019 May 17.
4
The past, present and future of potential small-molecule drugs targeting p53-MDM2/MDMX for cancer therapy.靶向 p53-MDM2/MDMX 的潜在小分子药物治疗癌症的过去、现在和未来。
Eur J Med Chem. 2019 Aug 15;176:92-104. doi: 10.1016/j.ejmech.2019.05.018. Epub 2019 May 8.
5
A phase I study of the HDM2 antagonist SAR405838 combined with the MEK inhibitor pimasertib in patients with advanced solid tumours.一项评估 HDM2 拮抗剂 SAR405838 联合 MEK 抑制剂 pimasertib 治疗晚期实体瘤患者的 I 期临床研究。
Br J Cancer. 2019 Feb;120(3):286-293. doi: 10.1038/s41416-018-0355-8. Epub 2018 Dec 26.
6
Targeted Degradation of MDM2 as a New Approach to Improve the Efficacy of MDM2-p53 Inhibitors.靶向降解 MDM2 作为提高 MDM2-p53 抑制剂疗效的新方法。
J Med Chem. 2019 Jan 24;62(2):445-447. doi: 10.1021/acs.jmedchem.8b01945. Epub 2018 Dec 21.
7
Discovery of MD-224 as a First-in-Class, Highly Potent, and Efficacious Proteolysis Targeting Chimera Murine Double Minute 2 Degrader Capable of Achieving Complete and Durable Tumor Regression.发现 MD-224 是一种首创的、高效能的、有效的蛋白酶体靶向嵌合体，可使鼠双微体 2 降解剂完全且持久地肿瘤消退。
J Med Chem. 2019 Jan 24;62(2):448-466. doi: 10.1021/acs.jmedchem.8b00909. Epub 2018 Dec 10.
8
The development of piperidinones as potent MDM2-P53 protein-protein interaction inhibitors for cancer therapy.哌啶酮类作为有效的 MDM2-P53 蛋白-蛋白相互作用抑制剂在癌症治疗中的发展。
Eur J Med Chem. 2018 Nov 5;159:1-9. doi: 10.1016/j.ejmech.2018.09.044. Epub 2018 Sep 18.
9
In vitro and in vivo characterization of a novel, highly potent p53-MDM2 inhibitor.一种新型高效p53-MDM2抑制剂的体外和体内特性研究
Bioorg Med Chem Lett. 2018 Nov 1;28(20):3404-3408. doi: 10.1016/j.bmcl.2018.08.027. Epub 2018 Aug 26.
10
Small Molecules Simultaneously Inhibiting p53-Murine Double Minute 2 (MDM2) Interaction and Histone Deacetylases (HDACs): Discovery of Novel Multitargeting Antitumor Agents.小分子同时抑制 p53-鼠双微体 2（MDM2）相互作用和组蛋白去乙酰化酶（HDACs）：新型多靶点抗肿瘤药物的发现。
J Med Chem. 2018 Aug 23;61(16):7245-7260. doi: 10.1021/acs.jmedchem.8b00664. Epub 2018 Aug 9.