Structural and Molecular Insight into the PWWP1 Domain of NSD2 from the Discovery of Novel Binders Via DNA-Encoded Library Screening

IF 4 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-08-25 DOI:10.1021/acsmedchemlett.5c00396

Gavin W. Collie*, Bryony Ackroyd, Catriona Corbishley, Daniel H. O’Donovan, Alex Edwards, Andrea Gohlke, Xiaoxiao Guo, Bethan Howells, Yuliang Li, Andrew Madin, Alexander G. Milbradt, Emma L. Rivers*, Sandeep K. Talapatra, Elizabeth Underwood and Alice Webb,

引用次数: 0

Abstract

NSD2 is a key epigenetic regulator and has received considerable attention as a drug target due to its well-documented role in tumorigenesis. We report here a DNA-encoded library screen targeting the PWWP1 domain of NSD2 from which we discovered novel, potent, and selective binders. Furthermore, these compounds were used to develop a novel crystal system, increasing our understanding of the folding of this domain. Together, these results provide a solid molecular and structural basis for the further study of the PWWP1 domain of NSD2 as a cancer drug target.

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通过dna编码文库筛选发现新的结合物，对NSD2的PWWP1结构域进行结构和分子研究

NSD2是一种关键的表观遗传调控因子，由于其在肿瘤发生中的作用已得到充分证实，因此作为药物靶点受到了相当大的关注。我们在此报告了一个针对NSD2的PWWP1结构域的dna编码文库筛选，从中我们发现了新的、有效的和选择性的结合物。此外，这些化合物被用来开发一种新的晶体体系，增加了我们对该结构域折叠的理解。总之，这些结果为进一步研究NSD2的PWWP1结构域作为癌症药物靶点提供了坚实的分子和结构基础。

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.