Discovery of new inhibitors of nuclease MRE11
Language English Country France Media print-electronic
Document type Journal Article
PubMed
39793442
DOI
10.1016/j.ejmech.2024.117226
PII: S0223-5234(24)01108-5
Knihovny.cz E-resources
- Keywords
- BRCA2, FEN1, MRE11 inhibitor, nuclease,
- MeSH
- MRE11 Homologue Protein * metabolism antagonists & inhibitors MeSH
- Enzyme Inhibitors * pharmacology chemistry chemical synthesis MeSH
- Humans MeSH
- Molecular Structure MeSH
- Drug Discovery MeSH
- DNA Repair drug effects MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- MRE11 Homologue Protein * MeSH
- Enzyme Inhibitors * MeSH
- MRE11 protein, human MeSH Browser
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.
CZ OPENSCREEN Institute of Molecular Genetics of the ASCR v v i Prague 4 Czech Republic
Department of Biology Faculty of Medicine Masaryk University 62500 Brno Czech Republic
Department of Chemistry Faculty of Science Masaryk University 62500 Brno Czech Republic
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