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

  • J Med Chem. 2025 Jun 12;68(11):11299-11321. doi: 10.1021/acs.jmedchem.5c00223.
Guozhang Xu  1 ,  Courtney G Havens  1 ,  Qiaolin Deng  1 ,  Cassandra Lowenstein  1 ,  Debangshu Samanta  1 ,  Brian Vidal  1 ,  Elham Behshad  1 ,  Mike Russell  1 ,  Peter Orth  1 ,  Cory T Rice  1 ,  Rakesh Nagilla  1 ,  Paul Kirchhoff  2 ,  Zhixiang Chen  2 ,  Rohan Kalyan Rej  2 ,  Ranjan Kumar Acharyya  2 ,  Dimin Wu  2 ,  Shaomeng Wang  2 ,  Weihong Zhang  1 ,  Wenxue Wu  1 ,  Larry Jolivette  1 ,  Corey Strickland  1 ,  Zhihua Sui  1 ,  Helai P Mohammad  1 ,  Xuqing Zhang  1 ,  E Scott Priestley  1
Affiliations
  • 1. SK Life Science Laboratories, 2500 Renaissance Boulevard, King of Prussia, Pennsylvania 19406, United States.
  • 2. The Rogel Cancer Center, Department of Internal Medicine, Department of Pharmacology, and Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States.
PMID: 40366756 DOI: 10.1021/acs.jmedchem.5c00223
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.

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