Discovery of ERD-3111 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. Herein, we report the discovery of a new class of potent and orally efficacious ERα degraders using the PROTAC technology with ERD-3111 being the most promising compound. ERD-3111 potently and effectively induced degradation of ERα protein in ER+ MCF-7 and T47D cells. Importantly, it achieved an excellent pharmacokinetic profile in rats, mice and dogs and good oral bioavailability in these species. ERD-3111 shows excellent microsomal stability and exhibits no significant hERG or CYP inhibition. PK/PD studies demonstrated that oral administration of ERD-3111 is highly effective in reducing the levels of wild-type and mutated ERα proteins in xenograft tumor tissues and achieves high plasma and tumor tissue exposures. Consistent with effective depletion of wild-type and ERα mutated proteins in tumor tissues, ERD-3111 demonstrates strong antitumor activity and is capable of achieving persistent tumor regression in the MCF-7 ER wild-type and ESR1D538G xenograft tumor models or 100% of tumor growth inhibition in the MCF-7 ESR1Y537S mutated xenograft tumor model. Significantly, ERD-3111 treatments did not cause animal weight loss or exhibit other signs of toxicity in mice. Taken together, our data show that ERD-3111 is a potent, orally bioavailable and highly efficacious ERα PROTAC degrader, and represents a promising lead compound for extensive evaluations for the treatment of ERα+ breast cancer.