作者: Kirchhoff, Paul D. ; Miao, Bukeyan ; Han, Xin ; McEachern, Donna ; Takyi-Williams, John ; Mckean, Robert ; Lu, Jianfeng ; Sun, Duxin ; Wang, Shaomeng ; Zhao, Lijie ; Wang, Yu ; Xu, Tianfeng ; Matvekas, Aleksas ; Wang, Lu ; Wen, Bo ; Wang, Mi ; Xiang, Weiguo ; Metwally, Hoda ; Yang, Chao-Yie ; Ator, Mark ; Qin, Chong
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 preclin. development for the treatment of AR + human cancers.