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.
- Resource Type
- Academic Journal
- Authors
- Han X; The Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States.; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States.; Zhao L; The Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States.; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States.; Xiang W; The Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States.; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States.; Miao B; The Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States.; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States.; Qin C; The Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States.; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States.; Wang M; The Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States.; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States.; Xu T; The Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States.; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States.; McEachern D; The Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States.; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States.; Lu J; The Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States.; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States.; Wang Y; The Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States.; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States.; Metwally H; The Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States.; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States.; Yang CY; The Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States.; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States.; Kirchhoff PD; The Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States.; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States.; Wang L; Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States.; Matvekas A; Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States.; Takyi-Williams J; Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States.; Wen B; Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States.; Sun D; Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States.; Ator M; Oncopia Therapeutics Inc, 2 West Liberty Blvd., Malvern, Pennsylvania 19355, United States.; Mckean R; Oncopia Therapeutics Inc, 2 West Liberty Blvd., Malvern, Pennsylvania 19355, United States.; Wang S; The Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States.; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States.; Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109, United States.; Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States.
- Source
- Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE
- Subject
- Language
- English
We report the discovery of ARD-2051 as a potent and orally efficacious androgen receptor (AR) proteolysis-targeting chimera degrader. ARD-2051 achieves DC 50 values of 0.6 nM and D max >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.