Discovery and Characterization of PVTX-321 as a Potent and Orally Bioavailable Estrogen Receptor Degrader for ER+/HER2– Breast Cancer

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.