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Updated: Sep 19, 2025

Protein Purification-free Method of Binding Affinity Determination by Microscale Thermophoresis
Published on: August 15, 2013
Allosteric Covalent Inhibitors of the STAT3 Transcription Factor from Virtual Screening
Tibor Viktor Szalai1,2,3, Vincenzo di Lorenzo1,2,4, Nikolett Péczka1,2,4
1Medicinal Chemistry Research Group, HUN-REN Research Centre for Natural Sciences, Magyar tudósok krt. 2, 1117 Budapest, Hungary.
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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