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合成致死性作为癌症新兴治疗方法:以使用沃纳综合征解旋酶(WRN)抑制剂为例

Synthetic Lethality as Emerging Treatment for Cancer: An Example by Using the Werner Syndrome Helicase (WRN) Inhibitors.

作者信息

Abdel-Magid Ahmed F

机构信息

Independent Consultant, 1383 Jasper Drive, Ambler, Pennsylvania 19002, United States.

出版信息

ACS Med Chem Lett. 2025 May 20;16(6):959-962. doi: 10.1021/acsmedchemlett.5c00272. eCollection 2025 Jun 12.

DOI:10.1021/acsmedchemlett.5c00272
PMID:40529098
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12169599/
Abstract

The invention in this patent application relates to chemical compounds represented herein generally by Formula 1a. These compounds are inhibitors of the Werner Syndrome ATP-dependent helicase (WRN) enzyme activity. The compounds of the invention may particularly be useful in treating cancers characterized by microsatellite instability (MSI) and/or defective DNA mismatch repair (dMMR) system.

摘要

本专利申请中的发明涉及一般由式1a表示的化合物。这些化合物是沃纳综合征ATP依赖性解旋酶(WRN)酶活性的抑制剂。本发明的化合物可能特别适用于治疗以微卫星不稳定性(MSI)和/或缺陷性DNA错配修复(dMMR)系统为特征的癌症。

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本文引用的文献

1
Structural Chemistry of Helicase Inhibition.解旋酶抑制的结构化学
J Med Chem. 2025 Feb 27;68(4):4022-4039. doi: 10.1021/acs.jmedchem.4c01909. Epub 2025 Feb 11.
2
Advances in synthetic lethality for cancer therapy: cellular mechanism and clinical translation.合成致死性在癌症治疗中的进展:细胞机制与临床转化。
J Hematol Oncol. 2020 Sep 3;13(1):118. doi: 10.1186/s13045-020-00956-5.
3
WRN helicase is a synthetic lethal target in microsatellite unstable cancers.WRN 解旋酶是微卫星不稳定癌症的合成致死靶点。
Nature. 2019 Apr;568(7753):551-556. doi: 10.1038/s41586-019-1102-x. Epub 2019 Apr 10.
4
Werner Syndrome Helicase Is Required for the Survival of Cancer Cells with Microsatellite Instability.微卫星不稳定的癌细胞存活需要沃纳综合征解旋酶
iScience. 2019 Mar 29;13:488-497. doi: 10.1016/j.isci.2019.02.006. Epub 2019 Mar 18.
5
Project DRIVE: A Compendium of Cancer Dependencies and Synthetic Lethal Relationships Uncovered by Large-Scale, Deep RNAi Screening.DRIVE 项目:通过大规模、深度 RNAi 筛选发现的癌症依赖性和合成致死关系概览。
Cell. 2017 Jul 27;170(3):577-592.e10. doi: 10.1016/j.cell.2017.07.005.
6
A Network of Conserved Synthetic Lethal Interactions for Exploration of Precision Cancer Therapy.用于精准癌症治疗探索的保守合成致死相互作用网络。
Mol Cell. 2016 Aug 4;63(3):514-25. doi: 10.1016/j.molcel.2016.06.022. Epub 2016 Jul 21.
7
Synthetic lethality: exploiting the addiction of cancer to DNA repair.合成致死性:利用癌细胞对 DNA 修复的依赖性。
Blood. 2011 Jun 9;117(23):6074-82. doi: 10.1182/blood-2011-01-313734. Epub 2011 Mar 25.