Abstract P4-04-04: Identification and development of oral estrogen receptor PROTAC degraders for breast cancer

ER-positive breast cancers comprise approximately 70-80% of all newly diagnosed cases. Downregulation or degradation of ER is a treatment approach currently used in the clinic to target estrogen receptor signaling. Faslodex, the only clinically-approved ER-downregulator, is administered as a monthly intramuscular injection with limiting pharmaceutical properties. Reasoning that an orally-available estrogen receptor degrader would be beneficial to patients, we have leveraged our experience in targeted protein degradation to generate and characterize novel proteolysis targeting chimeras (PROTACs) against estrogen receptor alpha. PROTACs are heterobifunctional molecules that facilitate the formation of a “trimer complex” comprised of the PROTAC, a pathogenic target protein of interest and an E3 ligase, which catalyzes the ubiquitylation and subsequent degradation of the target protein via the proteasome. To identify novel ER degraders (ER PROTACs), we have used several in vitro assays to characterize the extent of target engagement and receptor degradation. Potent ER PROTACs with good oral exposure and other pharmaceutical properties in multiple pre-clinical species were further evaluated in breast cancer xenograft models. Orally-administered ER PROTACs achieved >80% degradation of estrogen receptor alpha and demonstrated single agent tumor growth inhibition in these disease models. Further, combination with a CDK4/6 inhibitor resulted in the expected improvement in anti-proliferative activity. Citation Format: Flanagan JJ, Qian Y, Gough SM, Andreoli M, Bookbinder M, Bradley J, Rousseau E, Willard R, Crews CM, Crew AP, Taylor I, Houston J. Identification and development of oral estrogen receptor PROTAC degraders for breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-04-04.