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

Lijie Zhao; Xin Han; Jianfeng Lu; Donna McEachern; Shaomeng Wang

doi:10.1016/j.neo.2020.07.002

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.

Authors

Lijie Zhao¹, Xin Han², Jianfeng Lu², Donna McEachern², Shaomeng Wang³

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: shaomeng@umich.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Androgen Receptor Antagonists / pharmacology*
Animals
Apoptosis
Breast Neoplasms / drug therapy*
Breast Neoplasms / metabolism
Breast Neoplasms / pathology
Cell Cycle
Cell Movement
Cell Proliferation
Female
Gene Expression Regulation, Neoplastic / drug effects*
Humans
In Vitro Techniques
Mice
Mice, SCID
Piperidines / pharmacology*
Piperidines / therapeutic use
Proteolysis*
Pyrrolidines / pharmacology*
Pyrrolidines / therapeutic use
Receptors, Androgen / chemistry*
Thiazoles / pharmacology*
Thiazoles / therapeutic use
Tumor Cells, Cultured
Xenograft Model Antitumor Assays

Substances

AR protein, human
ARD-61
Androgen Receptor Antagonists
Piperidines
Pyrrolidines
Receptors, Androgen
Thiazoles

Grants and funding

P30 CA046592/CA/NCI NIH HHS/United States