A highly potent PROTAC androgen receptor (AR) degrader ARD-61 effectively inhibits AR-positive breast cancer cell growth in vitro and tumor growth in vivo

  • Neoplasia. 2020 Oct;22(10):522-532. doi: 10.1016/j.neo.2020.07.002.
Lijie Zhao  1 ,  Xin Han  2 ,  Jianfeng Lu  2 ,  Donna McEachern  2 ,  Shaomeng Wang  3
Affiliations
  • 1. School of Pharmaceutical Sciences and Institute of Drug Discovery & Development, Zhengzhou University, Zhengzhou 450001, China; Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, United States; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, United States.
  • 2. Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, United States; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, United States.
  • 3. Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, United States; Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, United States; Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, United States; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, United States. Electronic address: [email protected].
PMID: 32928363 DOI: 10.1016/j.neo.2020.07.002
Abstract

The Androgen Receptor (AR) has been found to be expressed in the majority of human breast Cancer and AR antagonists, such as enzalutamide, have shown promising clinical activity in AR-positive (AR+) breast Cancer. We have recently reported the discovery of a highly potent PROTAC AR degrader, ARD-61. In this study, we evaluated ARD-61 for its therapeutic potential and mechanism of action in breast Cancer models in vitro and in vivo. ARD-61 potently and effectively induces AR degradation in AR+ breast Cancer cell lines and is much more potent than enzalutamide in inhibition of cell growth and induction of cell cycle arrest and/or Apoptosis. ARD-61 effectively induces complete AR degradation in xenograft tumor tissue and is more effective than enzalutamide in achieving tumor growth inhibition in the MDA-MB-453 xenograft model in mice. Our study provides strong preclinical rationale to develop AR degraders for the treatment of AR+ human breast Cancer.

Keywords
Androgen-receptor (AR) degraders; Breast cancer; New therapeutic strategy.
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