Discovery of ARD-69 as a Highly Potent Proteolysis Targeting Chimera (PROTAC) Degrader of Androgen Receptor (AR) for the Treatment of Prostate Cancer

We
report herein the discovery of highly potent PROTAC degraders of androgen
receptor (AR), as exemplified by compound 34 (ARD-69).
ARD-69 induces degradation of AR protein in AR-positive prostate cancer
cell lines in a dose- and time-dependent manner. ARD-69 achieves DC50 values of 0.86, 0.76, and 10.4 nM in LNCaP, VCaP, and 22Rv1
AR+ prostate cancer cell lines, respectively. ARD-69 is capable of
reducing the AR protein level by >95% in these prostate cancer
cell lines and effectively suppressing AR-regulated gene expression.
ARD-69 potently inhibits cell growth in these AR-positive prostate
cancer cell lines and is >100 times more potent than AR antagonists.
A single dose of ARD-69 effectively reduces the level of AR protein
in xenograft tumor tissue in mice. Further optimization of ARD-69
may ultimately lead to a new therapy for AR+, castration-resistant
prostate cancer.