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

We report the discovery of ARD-2051as a potent and orally efficaciousandrogen receptor (AR) proteolysis-targeting chimera degrader. ARD-2051achieves DC50 values of 0.6 nM and D (max) >90% in inducing AR protein degradation in both theLNCaPand VCaP prostate cancer cell lines, potently and effectively suppressesAR-regulated genes, and inhibits cancer cell growth. ARD-2051 achievesa good oral bioavailability and pharmacokinetic profile in mouse,rat, and dog. A single oral dose of ARD-2051 strongly reduces AR proteinand suppresses AR-regulated gene expression in the VCaP xenografttumor tissue in mice. Oral administration of ARD-2051 effectivelyinhibits VCaP tumor growth and causes no signs of toxicity in mice.ARD-2051 is a promising AR degrader for advanced preclinical developmentfor the treatment of AR+ human cancers.

Automated summary

We report the discovery of ARD-2051, a highly potent and orally efficacious androgen receptor (AR) proteolysis-targeting chimera degrader. ARD-2051 demonstrates strong AR protein degradation activity and effectively suppresses AR-regulated genes in prostate cancer cell lines. It shows good oral bioavailability and pharmacokinetic profile in animal models. In addition, ARD-2051 inhibits tumor growth and exhibits no signs of toxicity in mice, making it a promising therapeutic option for AR+ human cancers.