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 <i>ESR1</i> mutations drive resistance to endocrine therapies. Heterobifunctional degraders (HBDs) targeting ERα offer a promising strategy to overcome this resistance. Here, we report PVTX-321 (<b>16a</b>), a potent ER HBD derived from a novel spirocyclic cereblon ligand and an ERα binder. PVTX-321 achieves a DC<sub>50</sub> of 0.15 nM in MCF-7 cells and acts as a strong antagonist (IC<sub>50</sub> = 59 nM), suppressing proliferation in ERα+ cell lines, including mutant variants (Y537S, D538G). It demonstrates favorable oral bioavailability, dose-dependent ERα degradation <i>in vivo</i> 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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Publication Details

Journal
Journal of Medicinal Chemistry
Published
2025-05-14
DOI
https://doi.org/10.1021/acs.jmedchem.5c00223
Citations
3
Primary Topic
Protein Degradation and Inhibitors
Type
article
Field-Weighted Citation Impact
2.42
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article

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

Larry J. Jolivette, Cassandra Lowenstein, Ranjan Kumar Acharyya, Elham Behshad et al.
3 citations
Journal of Medicinal Chemistry
Protein Degradation and Inhibitors
2.42
article

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

Larry J. Jolivette, Cassandra Lowenstein, Ranjan Kumar Acharyya, Elham Behshad, Rakesh Nagilla, Debangshu Samanta, Cory Rice, Rohan Kalyan Rej, E. Scott Priestley, Mike R. Russell, Qiaolin Deng, Xuqing Zhang, Courtney G. Havens, Peter Orth, Paul D. Kirchhoff, Shaomeng Wang, Wenxue Wu, Brian Vidal, Weihong Zhang, Zhixiang Chen, Guozhang Xu, Corey Strickland, Zhihua Sui, Dimin Wu, Helai P. Mohammad
article en
3 citations

Abstract

Estrogen receptor α (ERα) is a key therapeutic target in ER+/HER2- breast cancer, but <i>ESR1</i> mutations drive resistance to endocrine therapies. Heterobifunctional degraders (HBDs) targeting ERα offer a promising strategy to overcome this resistance. Here, we report PVTX-321 (<b>16a</b>), a potent ER HBD derived from a novel spirocyclic cereblon ligand and an ERα binder. PVTX-321 achieves a DC<sub>50</sub> of 0.15 nM in MCF-7 cells and acts as a strong antagonist (IC<sub>50</sub> = 59 nM), suppressing proliferation in ERα+ cell lines, including mutant variants (Y537S, D538G). It demonstrates favorable oral bioavailability, dose-dependent ERα degradation <i>in vivo</i> 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.

Journal of Medicinal ChemistryVol. 68(11)
University of Michigan (US), SK Life Science (United States) (US)
Zero hunger
Openalex Percentile: Top 12%
Protein Degradation and Inhibitors
2.42
DOISourceOpenAlex
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