Discovery of <b>ERD-3111</b> as a Potent and Orally Efficacious Estrogen Receptor PROTAC Degrader with Strong Antitumor Activity

Abstract

Estrogen receptor α (ERα) is a prime target for the treatment of ER-positive (ER+) breast cancer. Despite the development of several effective therapies targeting ERα signaling, clinical resistance remains a major challenge. In this study, we report the discovery of a new class of potent and orally bioavailable ERα degraders using the PROTAC technology, with <b>ERD-3111</b> being the most promising compound. <b>ERD-3111</b> exhibits potent in vitro degradation activity against ERα and demonstrates high oral bioavailability in mice, rats, and dogs. Oral administration of <b>ERD-3111</b> effectively reduces the levels of wild-type and mutated ERα proteins in tumor tissues. <b>ERD-3111</b> achieves tumor regression or complete tumor growth inhibition in the parental MCF-7 xenograft model with wild-type ER and two clinically relevant <i>ESR1</i> mutated models in mice. <b>ERD-3111</b> is a promising ERα degrader for further extensive evaluations for the treatment of ER+ breast cancer.