Abstract C57: Discovery and development of replication protein A (RPA)-DNA interaction inhibitors for cancer chemotherapy

Abstract

Abstract Platinum (Pt)-based chemotherapeutics exert their efficacy via the formation of DNA adducts which interfere with DNA replication, transcription and cell division and ultimately induce cell death. DNA repair of Pt-DNA adducts via nucleotide excision repair (NER) or homologous recombination repair (HRR) can substantially reduce the effectiveness of the Pt therapy, which is a major contributor for cellular resistance. Inhibition of these repair pathways, therefore, holds the potential to sensitize cancer cells to Pt-treatment and increase the clinical efficacy. Replication protein A (RPA) is a single-stranded DNA binding protein that plays a crucial role in the NER and HRR pathways apart from its role in replication and DNA damage checkpoint activation. We have pursued the development of small molecule inhibitors of the RPA-DNA interaction as a mechanism to target RPA activity and increase the efficacy of Pt-based cancer chemotherapy. We have developed an inhibitor, TDRL-551, that targets the central oligonucleotide/oligosaccharide binding folds in DNA binding domains A and B (DBD-A/B) of the 70 kDa RPA subunit. This lead compound shows synergy with cisplatin in tissue culture models of epithelial ovarian cancer (EOC) and in vivo efficacy, as a single agent as well as in a combination with platinum, in a lung cancer xenograft model. We have expanded our synthetic scheme and defined structure-activity relationships (SAR) towards optimization of TRDL-551 as an anticancer therapeutic for the treatment of lung and ovarian cancer. Supported by NIH grants R01 CA180710 and R41CA162648 to JJT. Citation Format: Navnath Gavande, Pamela S. VanderVere-Carozza, Akaash Mishra, John J. Turchi. Discovery and development of replication protein A (RPA)-DNA interaction inhibitors for cancer chemotherapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C57.