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RAD52 inhibitors for the treatment of cancer

DNA repair mechanisms play a critical role in the induction, malignant progression and treatment of cancer. As a result, pharmacological targeting of tumor-specific DNA repair pathways may amplify endogenous and drug-induced DNA damage and trigger apoptosis in cancer cells. DNA double strand breaks (DSBs), the most lethal DNA lesions, are usually repaired by two major DSB repair pathways: homologous recombination repair (HRR) and non-homologous end-joining (NHEJ). While NHEJ plays a major role in non-proliferating cells, HRR works predominantly on broken replication forks and usually depends on BRCA1-PALB2-BRCA2-RAD51 paralogs (BRCA)–RAD51 pathway.  In cells exhibiting genetic, epigenetic, and/or functional deficiencies in BRCA protein network, however, alternative HR mechanism such as RAD52-RAD51 pathway may emerge to protect cells from lethal effect of DSBs. RAD52 appears to be parallel with BRCA1/2 thus its inactivation should be synthetic lethal for BRCA1/2-mutated malignant cell lines. It has been demonstrated that inhibition of RAD52 DNA binding activity by small peptide aptamer exerted synthetic lethality in BRCA1 and BRCA2 mutated cancer cells and shRNA-mediated downregulation of RAD52 is lethal in tumor cell lines carrying BRCA2 inactivating mutations. Rad52 deletion in mice results only in mild phenotype without major impact on HR, and a peptide aptamer targeting RAD52 does not exert any detectable side effects in mice.  Therefore, RAD52 appears to be a promising target to trigger synthetic lethality in BRCA-deficient tumor cells without affecting normal cells. Our efforts are currently focused on the identification of novel small molecules capable of RAD52 DNA binding as potential therapies for BRCA linked cancers.

Temple University
Moulder Center for Drug Discovery Research

Temple University School of Pharmacy
3307 N Broad Street
Philadelphia, PA 19140