Development of Protein Degradation Inducers of Androgen Receptor by Conjugation of Androgen Receptor Ligands and Inhibitor of Apoptosis Protein Ligands

Targeted protein degradation using
small molecules is a novel strategy
for drug development. We have developed hybrid molecules named specific
and nongenetic inhibitor of apoptosis protein [IAP]-dependent protein
erasers (SNIPERs) that recruit IAP ubiquitin ligases to degrade target
proteins. Here, we show novel SNIPERs capable of inducing proteasomal
degradation of the androgen receptor (AR). Through derivatization
of the SNIPER­(AR) molecule at the AR ligand and IAP ligand and linker,
we developed 42a (SNIPER­(AR)-51), which shows effective
protein knockdown activity against AR. Consistent with the degradation
of the AR protein, 42a inhibits AR-mediated gene expression
and proliferation of androgen-dependent prostate cancer cells. In
addition, 42a efficiently induces caspase activation
and apoptosis in prostate cancer cells, which was not observed in
the cells treated with AR antagonists. These results suggest that
SNIPER­(AR)­s could be leads for an anticancer drug against prostate
cancers that exhibit AR-dependent proliferation.