Szalai Tibor Viktor, di Lorenzo Vincenzo, Péczka Nikolett, Mihalovits Levente M, Petri László, Ashraf Qirat F, de Araujo Elvin D, Honti Viktor, Bajusz Dávid, Keserű György M
Medicinal Chemistry Research Group, HUN-REN Research Centre for Natural Sciences, Magyar tudósok krt. 2, 1117 Budapest, Hungary.
National Drug Research and Development Laboratory, HUN-REN Research Centre for Natural Sciences, Magyar tudósok krt. 2, 1117 Budapest, Hungary.
ACS Med Chem Lett. 2025 May 6;16(6):991-997. doi: 10.1021/acsmedchemlett.4c00622. eCollection 2025 Jun 12.
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.
信号转导和转录激活因子（STAT）家族转录因子是重要的信号枢纽，其中有几种，特别是STAT3，已成为正在临床试验中研究的新兴癌靶标。STAT3的模块化结构表明其几个蛋白质结构域可能成为药物靶点，但迄今为止，利用潜在小分子抑制剂对它们的开发并不均衡，过去的研究高度倾向于保守的SH2结构域。在这里，我们针对卷曲螺旋结构域和DNA结合结构域交界处一个研究较少的结合位点，通过虚拟筛选发现了几种新的类先导共价抑制剂。通过结构导向的命中物扩展对最有利的命中化合物进行了探索，并优化成了一种低微摩尔浓度的抑制剂。这种化合物可作为未来探索性研究中针对该位点的化学生物学工具，或作为更高级先导优化阶段的基础。
