Allosteric Covalent Inhibitors of the STAT3 Transcription Factor from Virtual Screening

IF 4 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-05-06 DOI:10.1021/acsmedchemlett.4c0062210.1021/acsmedchemlett.4c00622

Tibor Viktor Szalai, Vincenzo di Lorenzo, Nikolett Péczka, Levente M. Mihalovits, László Petri, Qirat F. Ashraf, Elvin D. de Araujo, Viktor Honti, Dávid Bajusz and György M. Keserű*,

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Abstract

The STAT family of transcription factors are important signaling hubs, with several of them, particularly STAT3, being emerging oncotargets already investigated in clinical trials. The modular structure of STAT3 nominates several of its protein domains as possible drug targets, but their exploitation with potential small-molecule inhibitors has been unevenly distributed so far, with past efforts highly favoring the conserved SH2 domain. Here, we have targeted a sparsely studied binding site at the junction of the coiled-coil and DNA-binding domains and discovered several new lead-like covalent inhibitors by virtual screening. The most favorable hit compound has been explored via structure-guided hit expansion and optimized into a low micromolar inhibitor. This compound can serve as a chemical biology tool against this site in future exploratory studies or form the basis of a more advanced stage of lead optimization.

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STAT3转录因子的变构共价抑制剂的虚拟筛选

STAT转录因子家族是重要的信号中枢，其中一些，特别是STAT3，已经在临床试验中被研究为新兴的肿瘤共同靶点。STAT3的模块化结构提名了它的几个蛋白结构域作为可能的药物靶点，但到目前为止，它们与潜在的小分子抑制剂的开发分布不均匀，过去的研究高度倾向于保守的SH2结构域。在这里，我们针对一个研究较少的结合位点，在螺旋线圈和dna结合域的交界处，通过虚拟筛选发现了几个新的类似铅的共价抑制剂。通过结构导向的冲击扩展，探索了最有利的冲击化合物，并优化为低微摩尔抑制剂。该化合物可以作为未来探索性研究中针对该位点的化学生物学工具，或形成更高级的先导优化阶段的基础。

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.