Development of Inhibitors of RAD52 as a Therapy Against BRCA-Deficient Breast Cancer and Ovarian Cancer
Alexander V. Mazin, PhD, Professor, Department of Biochemistry and Molecular Biology,
Drexel University College of Medicine.
Lydia T. Komarnicky, MD, Professor and Chair, Department of Radiation Oncology, Drexel
University College of Medicine.
Patrick Y. S. Lam, PhD, Distinguished professor, Baruch S. Blumberg Institute
Dora Schnur, PhD, President, Doretta Discovery Services, LLC.
Dale B. Wigley, PhD, Fellow of Royal Society, Professor, Section of Structural Biology,
Department of Medicine, Imperial College, London, UK.
Breast cancer and ovarian cancer account for more than a quarter of all women’s cancers (1.7 million new cases worldwide annually). About 10% of all breast cancer and ovarian cancer cases are hereditary; nearly 50% of them caused by mutations in the BRCA1 and BRCA2 genes.
Recent studies showed that the viability of BRCA-deficient cancer cells depends on the function of RAD52 protein. Because in normal cells RAD52 mutants are viable, we propose to develop small-molecule inhibitors targeting RAD52 and use them to selectively eliminate BRCA deficient cancer cells. Previously, we identified 14 specific RAD52 inhibitors through high throughput screening using the biochemical assays; 7 of them showed activity in killing BRCA deficient cancer cells. Our goal is to improve the potency of the best RAD52 inhibitor (~10-fold) generating a drug-quality compounds suitable for development of a targeted monotherapy against BRCA-deficient cancers. Recently, PARP inhibitors were approved for BRCA-deficient ovarian cancers. Because PARP inhibitors and RAD52 inhibitors act through different mechanisms, we suggest that RAD52 inhibitors can also be used in combination with PARP inhibitors to increase the efficacy of anti-cancer therapy and to delay or reduce appearance of RARP-resistant cancers that have already been reported.