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.
Journal of medicinal chemistry. 2023 Jun 29 [Epub]
Xin Han, Lijie Zhao, Weiguo Xiang, Bukeyan Miao, Chong Qin, Mi Wang, Tianfeng Xu, Donna McEachern, Jianfeng Lu, Yu Wang, Hoda Metwally, Chao-Yie Yang, Paul D Kirchhoff, Lu Wang, Aleksas Matvekas, John Takyi-Williams, Bo Wen, Duxin Sun, Mark Ator, Robert Mckean, Shaomeng Wang
The Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States., Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States., Oncopia Therapeutics Inc, 2 West Liberty Blvd., Malvern, Pennsylvania 19355, United States.