Discovery of ARD-1676 as a Highly Potent and Orally Efficacious AR PROTAC Degrader with a Broad Activity against AR Mutants for the Treatment of AR + Human Prostate Cancer

We report herein the discovery and extensive characterization
of
ARD-1676, a highly potent and orally efficacious PROTAC degrader of
the androgen receptor (AR). ARD-1676 was designed using a new class
of AR ligands and a novel cereblon ligand. It has DC50 values
of 0.1 and 1.1 nM in AR+ VCaP and LNCaP cell lines, respectively,
and IC50 values of 11.5 and 2.8 nM in VCaP and LNCaP cell
lines, respectively. ARD-1676 effectively induces degradation of a
broad panel of clinically relevant AR mutants. ARD-1676 has an oral
bioavailability of 67, 44, 31, and 99% in mice, rats, dogs, and monkeys,
respectively. Oral administration of ARD-1676 effectively reduces
the level of AR protein in the VCaP tumor tissue in mice and inhibits
tumor growth in the VCaP mouse xenograft tumor model without any sign
of toxicity. ARD-1676 is a highly promising development candidate
for the treatment of AR+ human prostate cancer.