2. Academic Validation
  3. 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

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

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.
PMID: 37382562 DOI: 10.1021/acs.jmedchem.3c00405
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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