Drug repurposing screen targeting PARP identifies cytotoxic activity of efavirenz in high-grade serous ovarian cancer

Drug repurposing has potential to improve outcomes for high-grade serous ovarian cancer (HGSOC). Repurposing drugs with PARP family binding activity may produce cytotoxic effects through the multiple mechanisms of PARP including DNA repair, cell-cycle regulation, and apoptosis. The aim of this study was to determine existing drugs that have PARP family binding activity and can be repurposed for treatment of HGSOC. <i>In silico</i> ligand-based virtual screening (BLAZE) was used to identify drugs with potential PARP-binding activity. The list was refined by dosing, known cytotoxicity, lipophilicity, teratogenicity, and side effects. The highest ranked drug, efavirenz, progressed to <i>in vitro</i> testing. Molecularly characterized HGSOC cell lines, 3D hydrogel-encapsulated models, and patient-derived organoid models were used to determine the IC₅₀ for efavirenz, cell death, apoptosis, PARP1 enzyme expression, and activity in intact cancer cells following efavirenz treatment. The IC₅₀ for efavirenz was 26.43-45.85 μM for cells in two dimensions; 27.81 μM-54.98 μM in three dimensions, and 14.52 μM-42.27 μM in HGSOC patient-derived organoids. Efavirenz decreased cell viability via inhibition of PARP; increased CHK2 and phosphor-RB; increased cell-cycle arrest via decreased CDK2; increased γH2AX, DNA damage, and apoptosis. The results of this study suggest that efavirenz may be a viable treatment for HGSOC.