2. Academic Validation
  3. Discovery of new inhibitors of nuclease MRE11

Discovery of new inhibitors of nuclease MRE11

  • Eur J Med Chem. 2025 Mar 5:285:117226. doi: 10.1016/j.ejmech.2024.117226.
Fedor Nikulenkov 1,  Benoit Carbain 2,  Raktim Biswas 1,  Stepan Havel 3,  Jana Prochazkova 1,  Alexandra Sisakova 1,  Magdalena Zacpalova 1,  Melita Chavdarova 1,  Victoria Marini 1,  Vit Vsiansky 1,  Veronika Weisova 1,  Kristina Slavikova 1,  Dhanraj Biradar 3,  Prashant Khirsariya 3,  Marco Vitek 4,  David Sedlak 5,  Petr Bartunek 5,  Lukas Daniel 6,  Jan Brezovsky 6,  Jiri Damborsky 6,  Kamil Paruch 7,  Lumir Krejci 8
Affiliations

Affiliations

  • 1 Department of Biology, Faculty of Medicine, Masaryk University, 62500, Brno, Czech Republic.
  • 2 Department of Biology, Faculty of Medicine, Masaryk University, 62500, Brno, Czech Republic; Department of Chemistry, Faculty of Science, Masaryk University, 62500, Brno, Czech Republic.
  • 3 International Clinical Research Center, St. Anne's University Hospital in Brno, 62500, Brno, Czech Republic; Department of Chemistry, Faculty of Science, Masaryk University, 62500, Brno, Czech Republic.
  • 4 Department of Chemistry, Faculty of Science, Masaryk University, 62500, Brno, Czech Republic.
  • 5 CZ-OPENSCREEN, Institute of Molecular Genetics of the ASCR, v.v.i., Prague 4, Czech Republic.
  • 6 International Clinical Research Center, St. Anne's University Hospital in Brno, 62500, Brno, Czech Republic; Loschmidt Laboratories, Department of Experimental Biology and RECETOX, Faculty of Science, Masaryk University, 62500, Brno, Czech Republic.
  • 7 International Clinical Research Center, St. Anne's University Hospital in Brno, 62500, Brno, Czech Republic; Department of Chemistry, Faculty of Science, Masaryk University, 62500, Brno, Czech Republic. Electronic address: paruch@chemi.muni.cz.
  • 8 Department of Biology, Faculty of Medicine, Masaryk University, 62500, Brno, Czech Republic; NCBR, Faculty of Science, Masaryk University, 62500, Brno, Czech Republic. Electronic address: lkrejci@chemi.muni.cz.
PMID: 39793442 DOI: 10.1016/j.ejmech.2024.117226
Abstract

MRE11 nuclease is a central player in signaling and processing DNA damage, and in resolving stalled replication forks. Here, we describe the identification and characterization of new MRE11 inhibitors MU147 and MU1409. Both compounds inhibit MRE11 nuclease more specifically and effectively than the relatively weak state-of-the-art inhibitor mirin. They also abrogate double-strand break repair mechanisms that rely on MRE11 nuclease activity, without impairing ATM activation. Inhibition of MRE11 also impairs nascent strand degradation of stalled replication forks and selectively affects BRCA2-deficient cells. Herein, we illustrate that our newly discovered compounds MU147 and MU1409 can be used as chemical probes to further explore the biological role of MRE11 and support the potential clinical relevance of pharmacological inhibition of this nuclease.

Keywords

BRCA2; FEN1; MRE11 inhibitor; nuclease.

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