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

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.