Discovery of two structurally distinct classes of inhibitors targeting the nuclease MUS81 and enhancing efficacy of chemotherapy in cancer cells

Nucleases are emerging as promising pharmacological targets due to their essential role in maintaining genomic stability, which is crucial for cellular viability and can be exploited in the prevention and treatment of various diseases, including cancer. The conserved structure-specific endonuclease MUS81 is required for resolving branched DNA intermediates during replication, repair, and recombination. Aberrant activity of MUS81 leads to DNA damage, chromosomal abnormalities and genome instability, and contributes to oncogenesis. Pharmacological targeting of MUS81 thus represents an attractive underexplored therapeutic approach. Here we describe the discovery of two chemically distinct classes of small-molecule inhibitors of MUS81, exemplified by the compounds MU262 and MU876. Both compounds can effectively inhibit MUS81 in vitro and in the cell-based context and sensitize cancer cells to DNA-damaging agents through impairing their ability to repair DNA lesions. These compounds can be also used as chemical biology tools for further exploration of MUS81 function, and as leads in the process of drug discovery focused on development of new therapies that exploit DNA repair vulnerabilities in the treatment of cancer.