用小分子靶向错配修复缺陷癌症中的Werner综合征解旋酶

IF 4 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-05-16 DOI:10.1021/acsmedchemlett.5c0026210.1021/acsmedchemlett.5c00262

Robert B. Kargbo*,

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引用次数: 0

摘要

最近的研究已经确定了WRN解旋酶是错配修复缺陷（dMMR）癌症的关键依赖性。靶向WRN的小分子在微卫星高不稳定性（MSI-H）模型中显示出选择性活性。这些化合物通过破坏基因组维持途径损害肿瘤生长并促进癌细胞死亡，突出了一种有希望的治疗策略，用于基因定义的治疗耐药肿瘤。

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Targeting Werner Syndrome Helicase with Small Molecules in Mismatch Repair-Deficient Cancers

Recent efforts have identified WRN helicase as a critical dependency in mismatch repair-deficient (dMMR) cancers. Small molecules targeting WRN demonstrate selective activity in microsatellite instability-high (MSI-H) models. These compounds impair tumor growth and promote cancer cell death by disrupting genome maintenance pathways, highlighting a promising therapeutic strategy for genetically defined, treatment-resistant tumors.

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.