RD58

RD58 is a small molecule androgen receptor (AR) antagonist that was identified as a potent lead compound during the development of second-generation antiandrogens at the University of California, Los Angeles (UCLA). It is a structural analog of enzalutamide (MDV3100), sharing the same thiohydantoin core and dimethyl substitution at the 5-position, but lacking the fluorine atom on the benzamide ring. RD58 binds to the ligand-binding domain of the AR with high affinity, effectively inhibiting its nuclear translocation, DNA binding, and coactivator recruitment, which are essential for the progression of prostate cancer. Although enzalutamide was the analog ultimately selected for clinical development and approval, RD58 remains a significant research tool. Recent studies have utilized RD58 as a therapeutic payload in the creation of ferrous iron-activatable drug conjugates (FeADCs). These conjugates, such as TRX-RD58, are designed to selectively release RD58 in the presence of elevated labile iron (Fe2+) found in metastatic castration-resistant prostate cancer (mCRPC) cells, aiming to enhance tumor-specific delivery and reduce systemic toxicities, particularly those affecting the central nervous system.