Abstract A107: Development of polymerase theta inhibitors for precision medicine in BRCA-deficient cancers

DNA polymerase theta (Polq) is important for the proliferation of BRCA-deficient cancer cells, but is dispensable for normal cell growth. Thus, Polq is widely considered to be an important new drug target for BRCA-deficient cancers, such as those in the breast, ovary, prostate, pancreas, and blood. We have identified "expanded-size" nucleoside analogs that are uniquely incorporated by Polq and inhibit its activity. We have also identified small-molecule inhibitors of Polq through a random high-throughput screening approach. Consistent with the ability of Polq to promote the survival of BRCA-deficient cells, preliminary studies show that a newly identified Polq small-molecule inhibitor selectively kills cells deficient in BRCA2, while sparing wild-type cells. We are currently further advancing Polq nucleoside analog and small-molecule inhibitors via structure activity relationship (SAR) and medicinal chemistry studies with the goal of testing these inhibitors in BRCA-deficient PDX mouse models. Citation Format: Richard T. Pomerantz. Development of polymerase theta inhibitors for precision medicine in BRCA-deficient cancers [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A107.