2. Academic Validation
  3. Discovery of Two Structurally Distinct Classes of Inhibitors Targeting the Nuclease MUS81 and Enhancing Efficacy of Chemotherapy in Cancer Cells

Discovery of Two Structurally Distinct Classes of Inhibitors Targeting the Nuclease MUS81 and Enhancing Efficacy of Chemotherapy in Cancer Cells

  • J Med Chem. 2026 Mar 12;69(5):5350-5369. doi: 10.1021/acs.jmedchem.5c02096.
Jana Prochazkova 1,  Benoit Carbain 2 3,  Victoria Marini 1,  Fedor Nikulenkov 1,  Stepan Havel 2 3,  Naresh Akavaram 2,  Prashant Khirsariya 2 3,  Alexandra Sisakova 4,  Jakub Cibulka 1,  Michala Boudova 1,  Magdalena Zacpalova 1,  Magdalena Kalovska 1,  Joana Rodrigues 5,  Lukas Daniel 6,  Jan Brezovsky 6 7,  Petr Bartunek 8,  Claus Azzalin 5 9,  Kamil Paruch 2 3,  Lumir Krejci 1 4
Affiliations

Affiliations

  • 1 Department of Biology, Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic.
  • 2 Department of Chemistry, Faculty of Science, Masaryk University, 62500 Brno, Czech Republic.
  • 3 International Clinical Research Center, St. Anne's University Hospital, 656 91 Brno, Czech Republic.
  • 4 NCBR, Faculty of Science, Masaryk University, 62500 Brno, Czech Republic.
  • 5 GIMM - Gulbenkian Institute for Molecular Medicine, 1649-035 Lisbon, Portugal.
  • 6 Loschmidt Laboratories, Department of Experimental Biology and RECETOX, Faculty of Science, Masaryk University, 62500 Brno, Czech Republic.
  • 7 Laboratory of Biomolecular Interactions and Transport, Faculty of Biology, Department of Gene Expression, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, 61-614 Poznan, Poland.
  • 8 Institute of Molecular Genetics of the Czech Academy of Sciences, 14220 Prague, Czech Republic.
  • 9 Faculty of Medicine, University of Lisbon, 1649-028 Lisbon, Portugal.
PMID: 41740057 DOI: 10.1021/acs.jmedchem.5c02096
Abstract

Nucleases are promising pharmacological targets due to their essential role in maintaining genomic stability. They are crucial for regulation of cell viability, and their modulation is exploitable in disease prevention and treatment, including Cancer. The conserved structure-specific Endonuclease MUS81 resolves branched DNA intermediates during replication, repair, and recombination. Aberrant MUS81 activity causes DNA damage, chromosomal abnormalities, and genome instability, contributing to oncogenesis. Thus, pharmacological targeting of MUS81 is an attractive yet underexplored therapeutic strategy. We describe the discovery of two chemically distinct small-molecule classes of MUS81 inhibitors, exemplified by compounds MU262 and MU876. Both compounds effectively inhibit MUS81 in vitro and in cells, sensitizing Cancer cells to DNA-damaging agents by impairing DNA repair. These inhibitors can also serve as chemical biology tools for a deeper study of MUS81 function and as leads for drug discovery aimed at therapies exploiting DNA repair vulnerabilities in Cancer treatment.

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