Fragment-Based Discovery of Novel MUS81 Inhibitors

IF 4 3区医学 Q2 CHEMISTRY, MEDICINAL ACS Medicinal Chemistry Letters Pub Date : 2024-06-07 DOI:10.1021/acsmedchemlett.3c00453

Gavin W. Collie*, Ulf Börjesson, Yunhua Chen, Zhiqiang Dong, Paolo Di Fruscia, Andrea Gohlke, Anna Hoyle, Thomas A. Hunt, Mehul H. Jesani, Haiou Luo, Jakub Luptak, Alexander G. Milbradt, Priyanka Narasimhan, Martin Packer, Saleha Patel, Jingchuan Qiao, R. Ian Storer, Christopher J. Stubbs, Jonathan Tart, Caroline Truman, Anderson T. Wang, Matthew G. Wheeler and Jon Winter-Holt,

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Abstract

MUS81 is a structure-selective endonuclease that cleaves various branched DNA structures arising from natural physiological processes such as homologous recombination and mitosis. Due to this, MUS81 is able to relieve replication stress, and its function has been reported to be critical to the survival of many cancers, particularly those with dysfunctional DNA-repair machinery. There is therefore interest in MUS81 as a cancer drug target, yet there are currently few small molecule inhibitors of this enzyme reported, and no liganded crystal structures are available to guide hit optimization. Here we report the fragment-based discovery of novel small molecule MUS81 inhibitors with sub-μM biochemical activity. These inhibitors were used to develop a novel crystal system, providing the first structural insight into the inhibition of MUS81 with small molecules.

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基于片段发现新型 MUS81 抑制剂

MUS81 是一种结构选择性内切酶，能切割同源重组和有丝分裂等自然生理过程中产生的各种分支 DNA 结构。因此，MUS81 能够缓解复制压力，据报道，它的功能对许多癌症的存活至关重要，尤其是那些 DNA 修复机制失灵的癌症。因此，人们对将 MUS81 作为癌症药物靶点很感兴趣，但目前很少有关于这种酶的小分子抑制剂的报道，也没有配位晶体结构可用于指导靶点优化。在此，我们报告了基于片段发现的具有亚微米生化活性的新型小分子 MUS81 抑制剂。这些抑制剂被用于开发一种新型晶体系统，首次从结构上揭示了小分子对 MUS81 的抑制作用。

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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.

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