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.
- 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.
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.
-
Cat. No.Product NameDescriptionTargetResearch Area
-
Research Areas: Cancer