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-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.