ITRI-148

ITRI-148 is an orally bioavailable proteolysis-targeting chimera (PROTAC) designed for the treatment of advanced castration-resistant prostate cancer (CRPC). It specifically targets the N-terminal domain (NTD) of the androgen receptor (AR), a strategy that distinguishes it from traditional AR-targeted therapies that bind to the ligand-binding domain (LBD). By binding to a druggable pocket within the AR-NTD and recruiting the cereblon (CRBN) E3 ubiquitin ligase, ITRI-148 facilitates the formation of a ternary complex that leads to the selective proteasomal degradation of both full-length AR and AR splice variants, such as AR-V7. This mechanism is particularly significant because AR-V7 lacks the LBD and is a major driver of resistance to second-generation antiandrogens like enzalutamide. Preclinical studies have demonstrated that ITRI-148 maintains durable suppression of AR signaling, inhibits tumor growth in various xenograft models, and avoids the adaptive resistance typically seen with LBD-targeted agents.