Szalai, Tibor Viktor and Di Lorenzo, Vincenzo and Péczka, Nikolett and Mihalovits, Levente Márk and Petri, László and Ashraf, Qirat F. and de Araujo, Elvin D. and Honti, Viktor and Bajusz, Dávid and Keserű, György Miklós (2025) Allosteric Covalent Inhibitors of the STAT3 Transcription Factor from Virtual Screening. ACS MEDICINAL CHEMISTRY LETTERS, 16 (6). pp. 991-997. ISSN 1948-5875
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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. © 2025 The Authors. Published by American Chemical Society.
| Item Type: | Article |
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| Additional Information: | The authors received funding from the MSCA ITN ‘ALLODD’ [grant no. 956314 to G.M.K.], the Ministry of Culture and Innovation of Hungary [grant no. 2020-1.1.2-PIACI-KFI-2020-00039], the National Research Development and Innovation Office of Hungary [FK146063 to D.B., K135150 and PharmaLab (RRF-2.3.1-21-2022-00015) to G.M.K.] and the Schweizerische Nationalfonds (SNF) [MAPS 230109]. The National Laboratory of Biotechnology was supported by the Hungarian National Research, Development and Innovation Office-NKFIH through grant No. 2022-2.1.1-NL-2022-00008. The work of D.B. was supported by the János Bolyai Research Scholarship of the Hungarian Academy of Sciences. We acknowledge the HPC time and support of the Governmental Information Technology Development Agency, Hungary. |
| Uncontrolled Keywords: | virtual screening, covalent inhibitor, allosteric site, transcription factor, coiled-coil domain |
| Subjects: | R Medicine / orvostudomány > R1 Medicine (General) / orvostudomány általában |
| SWORD Depositor: | MTMT SWORD |
| Depositing User: | MTMT SWORD |
| Date Deposited: | 17 Sep 2025 19:35 |
| Last Modified: | 17 Sep 2025 19:35 |
| URI: | https://real.mtak.hu/id/eprint/224478 |
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