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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

2023; American Chemical Society; Volume: 66; Issue: 13 Linguagem: Inglês

10.1021/acs.jmedchem.3c00405

1520-4804

Xin Han, Lijie Zhao, Weiguo Xiang, Bukeyan Miao, Chong Qin, Mi Wang, Tianfeng Xu, Donna McEachern, Jianfeng Lü, Yu Wang, Hoda Metwally, Chao‐Yie Yang, Paul D. Kirchhoff, Lu Wang, Aleksas Matvekas, John Takyi‐Williams, Bo Wen, Duxin Sun, Mark A. Ator, Robert McKean, Shaomeng Wang,

Peptidase Inhibition and Analysis

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.