Abstract 1653: Design and synthesis of basic amino selective estrogen receptor degraders (BA-SERDs) for treatment-resistant breast cancer

Abstract About 1 in 8 United States women (about 12%) will develop invasive breast cancer during their lifespan. Approximately 40,000 women are expected to die from breast cancer each year. The largest single breast cancer subtype is defined as estrogen receptor alpha (ERα; ESR1) positive breast cancer (75%), wherein ERα played a critical role in cancer cell survival, proliferation and metastasis. The dysregulation of ER signaling formed the most important molecular event in the ER positive (ER+) breast cancer. Endocrine therapy (ET) had been successfully employed on such breast cancer patients and most of them had substantial reduced risks of breast cancer recurrence and mortality in the initial 5-10 years. However, the development of resistance to ET has the greatest impact on clinical use. The emergence of resistance is inevitable over time and will eventually become metastatic disease after long term of ET. Recent studies confirmed treatment failure of SERMs and AIs in ER+ metastatic settings, whereas ERα remains engaged in the advanced disease and contributes to disease pathogenesis. Fortunately, the treatment resistant breast cancer patients remain responsive to fulvestrant (ICI182,780) which has been described as a “pure antagonist” and caused ERα degradation as a SERD. Nonetheless, the pharmaceutical liabilities of fulvestrant including poor solubility and pharmacokinetics (PK) resulted in poor compliance. The clinical development of orally bioavailable SERDs i.e. GDC-0810, AZD9496, RAD1901 is needed to overcome these shortcomings. Herein, our lab identified a novel class of BA-SERDs to circumvent drug resistance. Citation Format: Yunlong Lu, Gregory R. Thatcher. Design and synthesis of basic amino selective estrogen receptor degraders (BA-SERDs) for treatment-resistant breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1653.