SM Gough

Abstract ARV-471, an estrogen receptor (ER) alpha PROTAC, is a hetero-bifunctional molecule that facilitates the interactions between estrogen receptor alpha and an intracellular E3 ligase complex, leading to the ubiquitylation and subsequent degradation of estrogen receptors via the proteasome. ARV-471 robustly degrades ER in ER-positive breast cancer cell lines with a half-maximal degradation concentration (DC50) of ˜ 2 nM. PROTAC-mediated ER degradation decreases the expression of classically-regulated ER-target genes (PR, GREB1, TFF) and inhibits cell proliferation of ER-dependent cell lines (MCF7, T47D). Additionally, ARV-471 degrades clinically-relevant ESR1 variants (Y537S and D538G) and inhibits growth of cell lines expressing those variants. In an immature rat uterotrophic model, ARV-471 degrades rat uterine ER and demonstrates no agonist activity. Daily, oral-administration of single agent ARV-471 (3, 10, and 30 mpk) leads to significant tumor volume regressions of estradiol-dependent MCF7 xenografts and concomitant tumor ER protein reductions of >90% at study termination. Moreover, when a CDK4/6 inhibitor is combined with ARV-471 in the MCF7 model, even more pronounced tumor growth inhibition is observed (˜130% TGI), accompanied by significant reductions in ER protein levels. In an ESR1 Y537S, hormone-independent patient-derived xenograft model, ARV-471 at 10 mpk completely inhibited growth and also reduced mutant ER protein levels. Taken together, the preclinical data of ARV-471 supports its continued development as a best-in-class oral ER PROTAC-degrader. Citation Format: Flanagan JJ, Qian Y, Gough SM, Andreoli M, Bookbinder M, Cadelina G, Bradley J, Rousseau E, Willard R, Pizzano J, Crews CM, Crew AP, Taylor I, Houston J. ARV-471, an oral estrogen receptor PROTAC degrader for breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-04-18.

Abstract 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.