502PBasic selective estrogen receptor degraders (B-SERDs) in combination with novel BET inhibitors in ER+ breast cancer

Abstract Background Resistance to endocrine therapy in estrogen receptor positive (ER+) breast cancer drives mortality and despite new targeted therapies, resistance is the obstacle to progression-free survival. Fulvestrant (FUL), a selective estrogen receptor degrader (SERD) was approved in 2017 for first-line therapy of metaststic disease in postmenopausal women; however, acquired FUL-resistance in both first-line setting and in combination therapy with CDK4/6 inhibitor, palbociclib, has been observed clinically. The poor pharmacokinetics of FUL may contribute to acquired resistance. Methods Using structure-based design, we optimized: 1) novel SERDs bearing a basic side chain (B-SERDs) as an orally bioavailable and brain penetrant alternative to FUL; 2) novel pyridinone-based bromodomains and extra-terminal motif (BET) inhibitors to be used in combination with B-SERDs or FUL. Biochemical assays and growth inhibition of breast cancer cell lines, resistant to tamoxifen, and/or FUL, both in 2D and 3D cultures were used to optimize and select development candidates. Drug metabolism and pharmacokinetics(DMPK) demonstrated oral bioavailability and dose selection for validation in mouse xenograft models of endocrine resistant breast cancer. Results B-SERDs showed equivalence to FUL in cell culture models, with respect to ERα degradation and antiproliferative activity; and in contrast to FUL, were demonstrated to have good oral and brain bioavailability. A development candidate with improved DMPK characteristics was effective in endocrine-resistant ER+ xenograft models. Novel BET inhibitors, optimized for potency in binding to BRD4-BD1 and selectivity over the larger family of bromodomain containing proteins, inhibited growth of tamoxifen and FUL-resistant breast cancer cells.Optimized compounds showed superior in vitro activity to eight BET inhibitors in clinical trials. The optimized BET inhibitor was validated alone and in combination with B-SERD in endocrine-resistant xenograft models. Conclusions The combination of B-SERD with BET inhibitor provides a multi-targeted suppression of ER signaling that may extend progression-free survival and cdircumvent acquired resistance in metastatic ER+ breast cancer. Legal entity responsible for the study Gregory R J Thatcher. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.