title: Structural basis for antagonism and resistance of bicalutamide in prostate cancer.
abstract: Carcinoma of the prostate is the most commonly diagnosed cancer in men. The current pharmacological treatment of choice for progressive androgen-dependent prostate cancer is the nonsteroidal antiandrogen, bicalutamide, either as monotherapy or with adjuvant castration or luteinizing hormone-releasing hormone superagonists to block the synthesis of endogenous testosterone. To date, no nonsteroidal or antagonist-bound androgen receptor (AR) structure is available. We solved the x-ray crystal structure of the mutant W741L AR ligand-binding domain bound to R-bicalutamide at 1.8-A resolution. This mutation confers agonist activity to bicalutamide and is likely involved in bicalutamide withdrawal syndrome. The three-dimensional structure demonstrates that the B ring of R-bicalutamide in the W741L mutant is accommodated at the location of the indole ring of Trp-741 in the WT AR bound to dihydrotestosterone. Knowledge of the binding mechanism for R-bicalutamide will provide molecular rationale for the development of new antiandrogens and selective AR modulators.
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, Ohio State University, Columbus, OH 43210, USA.
authors.forename: Casey E
authors.initials: CE
authors.lastname: Bohl
authors.forename: Wenqing
authors.initials: W
authors.lastname: Gao
authors.forename: Duane D
authors.initials: DD
authors.lastname: Miller
authors.forename: Charles E
authors.initials: CE
authors.lastname: Bell
authors.forename: James T
authors.initials: JT
authors.lastname: Dalton
mesh_terms: D000595:Amino Acid Sequence; D000726:Androgen Antagonists / Q000627:therapeutic use*; D000813:Anilides / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008297:Male; D008958:Models, Molecular; D009570:Nitriles; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D011944:Receptors, Androgen / Q000737:chemistry* / Q000187:drug effects / Q000235:genetics; D014105:Tosyl Compounds
chemical_list: D000726:Androgen Antagonists; D000813:Anilides; D000970:Antineoplastic Agents; D009570:Nitriles; D011944:Receptors, Androgen; D014105:Tosyl Compounds; C053541:bicalutamide