Tricyclic and Novel Chemotypes as Selective WRN Helicase Inhibitors for MSI-H Cancer Therapy

IF 4 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-08-15 DOI:10.1021/acsmedchemlett.5c00474

Robert B. Kargbo*,

引用次数: 0

Abstract

Recent advances targeting WRN helicase highlight a promising synthetic lethality approach for treating microsatellite instability-high (MSI-H) cancers. GlaxoSmithKline and Moma Therapeutics independently developed small molecule inhibitors with distinct chemotypes that disrupt WRN function. Their complementary efforts showcase differentiated selectivity, strategic molecular designs, and a shared focus on exploiting WRN dependency in DNA mismatch repair-deficient tumors.

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三环和新型化学型作为选择性WRN解旋酶抑制剂用于MSI-H癌症治疗

针对WRN解旋酶的最新进展强调了一种治疗微卫星不稳定性高（MSI-H）癌症的有希望的合成致死性方法。葛兰素史克（GlaxoSmithKline）和Moma Therapeutics独立开发了具有不同化学型的小分子抑制剂，可破坏WRN功能。他们的互补努力展示了差异化的选择性，战略性的分子设计，以及对DNA错配修复缺陷肿瘤中WRN依赖性的共同关注。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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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.