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Updated: Jun 30, 2026
An In Vivo Estrogen Deficiency Mouse Model for Screening Exogenous Estrogen Treatments of Cardiovascular Dysfunction After Menopause
Published on: August 13, 2019
Discovery and Characterization of PVTX-321 as a Potent and Orally Bioavailable Estrogen Receptor Degrader for
Guozhang Xu1, Courtney G Havens1, Qiaolin Deng1
1SK Life Science Laboratories, 2500 Renaissance Boulevard, King of Prussia, Pennsylvania 19406, United States.
Abstract:
Estrogen receptor α (ERα) is a key therapeutic target in ER+/HER2- breast cancer, but ESR1 mutations drive resistance to endocrine therapies. Heterobifunctional degraders (HBDs) targeting ERα offer a promising strategy to overcome this resistance. Here, we report PVTX-321 (16a), a potent ER HBD derived from a novel spirocyclic cereblon ligand and an ERα binder. PVTX-321 achieves a DC50 of 0.15 nM in MCF-7 cells and acts as a strong antagonist (IC50 = 59 nM), suppressing proliferation in ERα+ cell lines, including mutant variants (Y537S, D538G). It demonstrates favorable oral bioavailability, dose-dependent ERα degradation in vivo and induces tumor regression at 10 mg/kg (QD) in MCF-7 xenografts. With minimal CYP inhibition and a strong preclinical safety profile, PVTX-321 is a promising candidate for advancing ER+/HER2- breast cancer treatment.
