Unexpected binding orientation of bulky-B-ring anti-androgens and implications for future drug targets

摘要

Several new androgen receptor antagonists were synthesized and found to have varying activities across typically antiandrogen resistant mutants (Thr877 → Ala and Trp741 → Leu) and markedly improved potency over previously reported panantagonists. X-ray crystallography of a new anti-androgen in an androgen receptor mutant (Thr877 → Ala) shows that the receptor can accommodate the added bulk presented by phenyl to naphthyl substitution, casting doubt on previous reports of predicted binding orientation and the causes of antagonism in bulky-B-ring antagonists.