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

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

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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