Discovery of ARD-2051 as a Potent and Orally Efficacious Proteolysis Targeting Chimera (PROTAC) Degrader of Androgen Receptor for the Treatment of Advanced Prostate Cancer

  • J Med Chem. 2023 Jul 13;66(13):8822-8843. doi: 10.1021/acs.jmedchem.3c00405.
Xin Han  1  2 Lijie Zhao  1  2 Weiguo Xiang  1  2 Bukeyan Miao  1  2 Chong Qin  1  2 Mi Wang  1  2 Tianfeng Xu  1  2 Donna McEachern  1  2 Jianfeng Lu  1  2 Yu Wang  1  2 Hoda Metwally  1  2 Chao-Yie Yang  1  2 Paul D Kirchhoff  1  2 Lu Wang  3 Aleksas Matvekas  3 John Takyi-Williams  3 Bo Wen  3 Duxin Sun  3 Mark Ator  4 Robert Mckean  4 Shaomeng Wang  1  2  5  6
Affiliations
  • 1. The Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 2. Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 3. Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 4. Oncopia Therapeutics Inc, 2 West Liberty Blvd., Malvern, Pennsylvania 19355, United States.
  • 5. Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 6. Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States.
Abstract

We report the discovery of ARD-2051 as a potent and orally efficacious Androgen Receptor (AR) proteolysis-targeting chimera degrader. ARD-2051 achieves DC50 values of 0.6 nM and Dmax >90% in inducing AR protein degradation in both the LNCaP and VCaP prostate Cancer cell lines, potently and effectively suppresses AR-regulated genes, and inhibits Cancer cell growth. ARD-2051 achieves a good oral bioavailability and pharmacokinetic profile in mouse, rat, and dog. A single oral dose of ARD-2051 strongly reduces AR protein and suppresses AR-regulated gene expression in the VCaP xenograft tumor tissue in mice. Oral administration of ARD-2051 effectively inhibits VCaP tumor growth and causes no signs of toxicity in mice. ARD-2051 is a promising AR degrader for advanced preclinical development for the treatment of AR+ human cancers.

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