Abstract 44: The discovery of ARV-471, an orally bioavailable estrogen receptor degrading PROTAC for the treatment of patients with breast cancer

Abstract

ARV-471, an estrogen receptor (ER) alpha PROTAC® protein degrader, 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 ~ 1 nM. PROTAC® mediated ER degradation decreases the expression of classically regulated ER-target genes 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 anti-tumor activity 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 (131% 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 significantly 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® protein degrader. These preclinical data supported the clinical development of ARV-471 for the treatment of patients with breast cancer. The discovery, chemical structure and initial clinical data of ARV-471 will be presented. Citation Format: Lawrence B. Snyder, John J. Flanagan, Yimin Qian, Sheryl M. Gough, Monica Andreoli, Mark Bookbinder, Gregory Cadelina, John Bradley, Emma Rousseau, Julian Chandler, Ryan Willard, Jennifer Pizzano, Craig M. Crews, Andrew P. Crew, John Houston, Marcia Dougan Moore, Ron Peck, Ian Taylor. The discovery of ARV-471, an orally bioavailable estrogen receptor degrading PROTAC for the treatment of patients with breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 44.

Update Breast Cancer 2021 Part 5 – Advanced Breast Cancer

“…In a phase I trial, objective response was achieved in 4 out of 14 pa-tients with advanced breast cancer and massive prior treatment. None of the patients experienced primary progression [15].…”

“…2). ARV-471 is a PROTAC targeted against the oestrogen receptor [15]. In a phase I trial, objective response was achieved in 4 out of 14 pa-tients with advanced breast cancer and massive prior treatment.…”

“…2 ). Mit ARV-471 gibt es ein PROTAC, welches gegen den Östrogenrezeptor gerichtet ist 15 . In einer Phase-I-Studie konnte bei 4 von 14 stark vorbehandelten Patientinnen mit fortgeschrittenem Mammakarzinom ein objektives Ansprechen erreicht werden.…”

Update Breast Cancer 2021 Part 4 – Prevention and Early Stages

“…The field of oral SERDs has seen some new developments, such as the use of PROTAC (Proteolysis Targeting Chimera) technology 54 . These hetero-bifunctional molecules bind a ligand for a protein of interest (in this case the oestrogen receptor) on one side and the E3 ubiquitin ligase complex on the other.…”

“…Im Bereich der oralen SERDs gibt es einige Neuentwicklungen, wie z. B. die Nutzung der PROTAC-(Proteolysis-Targeting-Chimera-)Technologie 54 . Diese hetero-bifunktionalen Moleküle binden auf der einen Seite einen Liganden für ein Protein von Interesse (in diesem Fall den Östrogenrezeptor) und auf der anderen Seite den E3-Ubiquitin-Ligase-Komplex.…”