Circumventing anti-androgen resistance by molecular design.

Nuclear/steroid hormone receptors (NHRs) function as ligand-dependent transcriptional regulators of diverse sets of genes involved in development and homeostasis. Mutations to the androgen receptor (AR), a member of NHRs, have been linked to the failure of hormonal therapy in the treatment of prostate cancer (PCa). It has been proposed that AR mutations such as Thr877 → Ala, Trp741 → Leu and Trp741 → Cys that cause anti-androgens such as flutamide and bicalutamide to function as agonists are likely associated with anti-androgen withdrawal syndrome in PCa therapy. The recently solved crystal structure of bicalutamide was used to design analogs that would complement the Trp741 → Leu mutation effectively restoring antagonist action of the ligand. Three out of the six designed analogs showed potent antagonistic activity in all three mutations as well as wild-type, suggesting that these analogs may be considered “pan-antagonists” of AR.