Discovery of ARD-2585 as an Exceptionally Potent and Orally Active PROTAC Degrader of Androgen Receptor for the Treatment of Advanced Prostate Cancer

We
report herein the discovery of exceptionally potent and orally
bioavailable PROTAC AR degraders with ARD-2585 being the most promising
compound. ARD-2585 achieves DC50 values of ≤0.1
nM in the VCaP cell line with AR gene amplification and in the LNCaP
cell line carrying an AR mutation. It potently inhibits cell growth
with IC50 values of 1.5 and 16.2 nM in the VCaP and LNCaP
cell lines, respectively, and achieves excellent pharmacokinetics
and 51% of oral bioavailability in mice. It is more efficacious than
enzalutamide in inhibition of VCaP tumor growth and does not cause
any sign of toxicity in mice. ARD-2585 is a promising AR degrader
for extensive investigations for the treatment of advanced prostate
cancer.