Structural basis for antagonism and resistance of bicalutamide in prostate cancer.
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.
Bohl
Casey E
CE
Division of Pharmaceutics, College of Pharmacy, Ohio State University, Columbus, OH 43210, USA.
Gao
Wenqing
W
Miller
Duane D
DD
Bell
Charles E
CE
Dalton
James T
JT
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
D000726:Androgen Antagonists; D000813:Anilides; D000970:Antineoplastic Agents; D009570:Nitriles; D011944:Receptors, Androgen; D014105:Tosyl Compounds; C053541:bicalutamide