Definition

An orally available androgen receptor (AR)-targeted protein degrader, using the proteolysis targeting chimera (PROTAC) technology, with potential antineoplastic activity. HP518 is composed of an AR ligand attached to an E3 ligase recognition moiety. Upon oral administration of AR degrader HP518, the AR-binding moiety specifically targets and binds to AR, particularly AR with AR ligand-binding domain (LBD) mutations. E3 ligase is recruited to the AR by the E3 ligase recognition moiety and the AR target protein is tagged by ubiquitin. This causes ubiquitination and degradation of AR by the proteasome. This prevents the expression of AR target genes and halts AR-mediated signaling. This results in an inhibition of proliferation in AR-overexpressing tumor cells. AR, a hormone-regulated transcription factor, plays a key role in tumor cell proliferation in castration-resistant prostate cancer (CRPC).