RAD51-targeting small molecule degrader sensitizes BRCA-proficient prostate cancer cells to PARP inhibitors via synthetic lethality.

Poly (ADP-ribose) polymerase (PARP) inhibitors though effective in patients with homologous recombination (HR)-deficient tumors, a large population of patients remain unresponsive, primarily due to either the absence of HR-related mutation or the restoration of HR functionality. RAD51, a critical protein in HR repair signaling that ensures precise DNA lesion repair, represents a promising therapeutic target. Inspired by the clinical success of PARP inhibitors in treating BRCA1/2-mutant cancers and leveraging the potential of proteolysis-targeting chimeras (PROTAC) technology-a method that exploits the cell's protein degradation machinery to eliminate disease-associated proteins, we generated a small-molecule PROTAC G73. This compound degrades RAD51 in a concentration- and time-dependent manner, effectively mimicking the HR-deficient phenotype by impairing DNA double-strand break (DSB) repair. Furthermore, G73-mediated RAD51 degradation synergizes with the PARP inhibitor olaparib, inducing synthetic lethality and re-sensitizing olaparib-resistant cancers to PARP inhibition. This fully small-molecule-based strategy presents a compelling strategy to overcome resistance to PARP inhibitors, expanding their therapeutic potential beyond patients with HR-deficient tumors.