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Homologous recombination (HR) is the principal pathway for the error-free repair of DNA double-strand breaks (DSBs) and other most harmful DNA lesions. Deficiencies in HR cause genome destabilization and lead to tumorigenesis. About 50% of familial breast and ovarian cancers are caused by mutations in the BRCA1 and BRCA2 genes, key members of the HR pathway. HR deficiency forces tumor cells to rely on alternative intact DNA repair pathways, such that inactivation of these pathways induces synthetic lethality. Targeting DNA repair proteins in synthetically lethal relationships has emerged as a prime strategy of novel cancer therapeutics. Our work is focused on the development of small molecule inhibitors of the HR protein RAD52. While mutations in RAD52 cause no discernible HR phenotype in normal human cells, inactivation of RAD52 in BRCA1/BRCA2-deficient cancer cells results in cell death. This synthetically lethal BRCA/RAD52 relationship renders RAD52 a promising therapeutic target. We have developed small molecule inhibitors of RAD52 (RAD52i) and demonstrated the in vitro inhibition of RAD52's biochemical activities of DNA annealing and DNA strand exchange with an IC50 in the high nanomolar range. In vivo, we show RAD52i exhibit anti-neoplastic activity on BRCA-deficient cancer cells. We will use RAD52 inhibitors to develop novel cancer therapies as well as tools to study the mechanisms of HR in humans. R01 GM136717, R01 CA23728 (A.V.M.). Congressionally Directed Medical Research Programs BC191160 (AV.M.) A.V.M. is the holder of the Joe R. and Teresa Lozano Long Chair in Cancer Research and is recipient of a CPRIT REI Award (RR210023) and UT System Faculty STARs Award
Rossi et al. (Fri,) studied this question.