2. Academic Validation
  3. Allosteric Covalent Inhibitors of the STAT3 Transcription Factor from Virtual Screening

Allosteric Covalent Inhibitors of the STAT3 Transcription Factor from Virtual Screening

  • ACS Med Chem Lett. 2025 May 6;16(6):991-997. doi: 10.1021/acsmedchemlett.4c00622.
Tibor Viktor Szalai 1 2 3,  Vincenzo di Lorenzo 1 2 4,  Nikolett Péczka 1 2 4,  Levente M Mihalovits 1 2,  László Petri 1 2,  Qirat F Ashraf 5,  Elvin D de Araujo 6,  Viktor Honti 7,  Dávid Bajusz 1 2,  György M Keserű 1 2 4
Affiliations

Affiliations

  • 1 Medicinal Chemistry Research Group, HUN-REN Research Centre for Natural Sciences, Magyar tudósok krt. 2, 1117 Budapest, Hungary.
  • 2 National Drug Research and Development Laboratory, HUN-REN Research Centre for Natural Sciences, Magyar tudósok krt. 2, 1117 Budapest, Hungary.
  • 3 Department of Inorganic and Analytical Chemistry, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, Műegyetem rkp. 3, H-1111 Budapest, Hungary.
  • 4 Department of Organic Chemistry and Technology, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, Műegyetem rkp. 3, H-1111 Budapest, Hungary.
  • 5 Department of Chemical & Physical Sciences, University of Toronto Mississauga, Mississauga, ON L5L 1C6, Canada.
  • 6 Centre for Medicinal Chemistry, University of Toronto at Mississauga, Mississauga, ON L5L 1C6, Canada.
  • 7 HUN-REN Biological Research Centre, Institute of Genetics, Drosophila Blood Cell Differentiation Group, 62. Temesvári krt., 6726 Szeged, Hungary.
PMID: 40529081 DOI: 10.1021/acsmedchemlett.4c00622
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.

Keywords

Virtual screening; allosteric site; coiled-coil domain; covalent inhibitor; transcription factor.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-174386
    STAT3 Inhibitor