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

• Published in: Journal of medicinal chemistry 2023-07, Vol.66 (13), p.8822-8843
• Main Authors: Han, Xin, Zhao, Lijie, Xiang, Weiguo, Miao, Bukeyan, Qin, Chong, Wang, Mi, Xu, Tianfeng, McEachern, Donna, Lu, Jianfeng, Wang, Yu, Metwally, Hoda, Yang, Chao-Yie, Kirchhoff, Paul D., Wang, Lu, Matvekas, Aleksas, Takyi-Williams, John, Wen, Bo, Sun, Duxin, Ator, Mark, Mckean, Robert, Wang, Shaomeng
• Format: Article
• Language: English
• Subjects: Animals; Cell Line, Tumor; Dogs; Humans; Male; Mice; Prostatic Neoplasms - pathology; Proteolysis; Proteolysis Targeting Chimera; Rats; Receptors, Androgen - metabolism
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.3c00405

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 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.