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Discovery of ERD-3111 as a Potent and Orally Efficacious Estrogen Receptor PROTAC Degrader with Strong Antitumor
Zhixiang Chen1, Biao Hu1, Rohan Kalyan Rej1
1Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan, Ann Arbor, Michigan 48109, United States.
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 ERD-3111 being the most promising compound. ERD-3111 exhibits potent in vitro degradation activity against ERα and demonstrates high oral bioavailability in mice, rats, and dogs. Oral administration of ERD-3111 effectively reduces the levels of wild-type and mutated ERα proteins in tumor tissues. ERD-3111 achieves tumor regression or complete tumor growth inhibition in the parental MCF-7 xenograft model with wild-type ER and two clinically relevant ESR1 mutated models in mice. ERD-3111 is a promising ERα degrader for further extensive evaluations for the treatment of ER+ breast cancer.
Insights
Researchers developed ERD-3111, a new orally available Estrogen Receptor Alpha (ERα) degrader using PROTAC technology. This compound effectively reduces ERα protein levels and inhibits tumor growth in ER-positive breast cancer models.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Estrogen Receptor Alpha (ERα) is a key target for ER-positive breast cancer treatment.
- Clinical resistance to current ERα-targeted therapies presents a significant challenge.
- Novel therapeutic strategies are needed to overcome resistance and improve patient outcomes.
Purpose of the Study:
- To discover and characterize novel ERα degraders with potential for treating ER-positive breast cancer.
- To evaluate the efficacy and pharmacokinetic properties of a new class of PROTAC-based ERα degraders.
- To assess the therapeutic potential of ERD-3111 in preclinical models of ER-positive breast cancer.
Main Methods:
- Development of Proteolysis Targeting Chimeras (PROTACs) to induce ERα degradation.
- In vitro assessment of ERα degradation activity.
- Pharmacokinetic studies in mice, rats, and dogs to determine oral bioavailability.
- In vivo efficacy studies using xenograft models of ER-positive breast cancer, including wild-type and ESR1-mutated variants.
Main Results:
- Discovery of ERD-3111, a potent and orally bioavailable ERα degrader.
- ERD-3111 demonstrated effective degradation of both wild-type and mutated ERα proteins in tumor tissues.
- Significant tumor regression or growth inhibition was observed in multiple preclinical breast cancer models upon oral administration of ERD-3111.
Conclusions:
- ERD-3111 represents a promising new therapeutic candidate for ER-positive breast cancer.
- The compound's potent ERα degradation and favorable pharmacokinetic profile warrant further clinical evaluation.
- PROTAC technology offers a viable strategy for developing novel treatments against ERα-driven cancers, including resistant forms.
