Abstract P2-08-11: An orally bioavailable selective estrogen receptor downregulator

Abstract

Abstract Orally bioavailable selective estrogen receptor downregulators (SERDs) may offer greater systemic drug exposure, improved clinical efficacy, and more durable treatment outcome for breast cancer patients with disease progression following antiestrogen or aromatase inhibitor therapy. We report the design and synthesis of ZB716, a C-3 position boronic acid modified fulvestrant, which behaves as a steroidal SERD suitable for oral administration. ZB716 binds to ERa competitively at an IC50 of 4.1 nM as compared to 3.9 nM for fulvestrant, and it effectively downregulates ERa (IC50=12.7 nM) in both tamoxifen-sensitive (T47D) and tamoxifen-resistant (T47D/PKCa) breast cancer cells. It acts as an antiestrogen that exerts potent antiproliferative effects on tamoxifen-resistant breast cancer cells (MCF-7/TamR, T47D/PKCa, and T47D/Y537S). When orally administered to mice, rats, and Beagle dogs, ZB716 demonstrates superior oral bioavailability in all animal-based pharmacokinetic studies when compared to fulvestrant administered by subcutaneous injection. More importantly, orally administered ZB716 was found to potently inhibit xenograft tumor growth in mice. These pre-clinical data strongly suggest that ZB716 is a promising SERD drug that could offer significant improvement over existing SERD regimen of Faslodex. ZB716 is being prepared in an IND application for phase 1 clinical trial in ER+, HER2- advanced breast cancer patients. Citation Format: Wang G, Liu J, Zheng S, Miele L, Wiese T, Zhong Q, Guo S. An orally bioavailable selective estrogen receptor downregulator [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-08-11.