ARD-2065

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 preclin. development for the treatment of AR + human cancers.