Targeting androgen receptor nuclear localization in prostate cancer

Project Summary Title: Targeting androgen receptor nuclear localization in prostate cancer Prostate cancer (PCa) is the most frequently diagnosed cancer and second leading cause of cancer death in American men. More effective therapies for PCa are urgently needed. The androgen receptor (AR) is a key therapeutic target for PCa. AR appears to be overexpressed, stabilized, and nuclear-localized in castration- resistant PCa (CRPC). AR nuclear localization is necessary for its function as a transcription factor. We have developed a high-throughput screen and identified two closely related pyrroloimidazoles, CPPI and EPPI, which can inhibit AR nuclear localization in CRPC. These small molecules inhibited all tested AR-positive prostate cancer cells, including enzalutamide-resistant CRPC. Further studies suggested that these small molecules can directly bind to AR and enhance AR ubiquitination and degradation in the nucleus, acting as nuclear AR degraders (NARDs). Since CRPC is associated with increased AR level and stability, inhibition or even partial inhibition of AR level may slow down the progression to CRPC. Here, we hypothesize that NARD can inhibit CRPC and prostate cancer progression to castration resistance. Also, NARD may enhance the efficacy of other AR targeting agents because resistance to AR targeting agents is also associated with increased AR expression. To explore the therapeutic potential of NARD, 3 specific aims are proposed. Aim 1 will determine the mechanisms by which CPPI inhibits AR nuclear localization in CRPC cells. Aim 2 will evaluate potential synergies of CPPI with other AR-targeting approaches. Aim 3 will synthesize and characterize novel analogues of CPPI with the goal to identify new lead NARD compounds with submicromolar potency and high specificity for AR-positive PCa cells. Success of the proposed project may lead a strategy to slow down the progression of prostate cancer to castration resistance and to an alternative approach to PROTAC AR degraders, which are being actively investigated as a therapeutic agent for AR-positive CRPC. Since the mechanisms of NARD action are different from PROTAC-type AR degraders, NARD may be more suitable than PROTAC AR degraders in certain patient populations.