Development of pan-antagonists of mutant androgen receptors associated with antiandrogen resistant prostate cancer.

摘要

Prostate cancer remains one of the most commonly diagnosed cancers in men. The effectiveness of anti-androgens in the treatment of advanced prostate cancer is well known. However, 20%-50% patients become resistant to antiandrogen treatment within five years, a state referred to as antiandrogen resistant prostate cancer (ARPC) or castration resistant prostate cancer (CRPC). Androgen Receptor (AR) Thr877→Ala and Trp741→L mutations have been found in patients who become resistance to antiandrogens, flutamide and bicalutamide, respectively.;Using structure based drug design, the second generation pan-antagonists were designed specifically to be universal antagonists that target not only wild-type AR, but also flutamide and bicalutamide resistant mutants of AR. Based on the known proposed model of active antagonist action, a series of expanded arylsulfone based pan-antagonists with or without long chain extensions were synthesized and SAR studies were carried out. With long chain extensions several ligands, PAN22, PAN52 and PAN62, retained high binding affinities with both mutant and wild-type AR as well as showing pure antagonist activities in cell based assays. These are the first examples of anti-androgens with long polar extensions that are modeled to extend to the receptor surface and directly block coactivator recruitment. The ligand, PAN52, was further investigated in LNCaP clonogenic assays and can evade in vitro foci formation under condition where bicalutamide shows significant foci formation and which mimic the development of ARPC. These results suggest that PAN52 or similar analogs might be effective in delaying and/or reducing the occurance of anti-androgen resistant prostate cancer.