Strategies toward Discovery of Potent and Orally Bioavailable Proteolysis Targeting Chimera Degraders of Androgen Receptor for the Treatment of Prostate Cancer

Proteolysis
targeting chimera (PROTAC) small-molecule degraders
have emerged as a promising new type of therapeutic agents, but the
design of PROTAC degraders with excellent oral pharmacokinetics is
a major challenge. In this study, we present our strategies toward
the discovery of highly potent PROTAC degraders of androgen receptor
(AR) with excellent oral pharmacokinetics. Employing thalidomide to
recruit cereblon/cullin 4A E3 ligase and through the rigidification
of the linker, we discovered highly potent AR degraders with good
oral pharmacokinetic properties in mice with ARD-2128 being the best
compound. ARD-2128 achieves 67% oral bioavailability in mice, effectively
reduces AR protein and suppresses AR-regulated genes in tumor tissues
with oral administration, leading to the effective inhibition of tumor
growth in mice without signs of toxicity. This study supports the
development of an orally active PROTAC AR degrader for the treatment
of prostate cancer and provides insights and guidance into the design
of orally active PROTAC degraders.