Learning From Estrogen Receptor Antagonism: Structure-Based Identification of Novel Antiandrogens Effective Against Multiple Clinically Relevant Androgen Receptor Mutants

Current treatment strategy for advanced prostate cancer is to suppress androgen receptor (AR) by castration and antiandrogens. However, several clinically relevant AR mutations cause insensitivity to current antiandrogens and convert them into agonists. We aim to identify full AR antagonists even for AR mutants. As crystal structure of AR ligand-binding domain (LBD) at antagonistic form is not available, we decided to learn from estrogen receptor (ER) antagonism: (i) We built a structural model of wild-type AR-LBD complexed with antiandrogen bicalutamide (wild type/bicalutamide) using ERa-LBD/hydroxytamoxifen structure as the template for helix-12. (ii) By comparative structural analysis of 24 ERa-LBD complexes, we found residues D351 and L354 at helix-3 adopt unique conformations, and distance between them is a marker of ERa-LBD/antagonist complexes. The AR residues corresponding to D351 and L354 are E709 and L712, respectively. We found distance between E709 and L712 of the wild type/bicalutamide model is substantially different from that of AR-LBD/agonist complexes, suggesting this distance could be a marker of antagonistic AR-LBD, which was supported by molecular dynamics simulations. Based on the wild type/bicalutamide model, we discovered compound 3 is a novel antiandrogen effective against the wild type and T877A-, W741C-, and H874Y-mutated androgen receptors. We found compound 3 has dual functions, inhibiting androgen receptor and IKK beta.