Structural basis for antagonism and resistance of bicalutamide in prostate cancer

DOI Web Site 被引用文献18件
  • Casey E. Bohl
    Division of Pharmaceutics, College of Pharmacy, Ohio State University, Columbus, OH 43210; Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee, Memphis, TN 38163; and Department of Molecular and Cellular Biochemistry, College of Medicine and Public Health, Ohio State University, Columbus, OH 43210
  • Wenqing Gao
    Division of Pharmaceutics, College of Pharmacy, Ohio State University, Columbus, OH 43210; Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee, Memphis, TN 38163; and Department of Molecular and Cellular Biochemistry, College of Medicine and Public Health, Ohio State University, Columbus, OH 43210
  • Duane D. Miller
    Division of Pharmaceutics, College of Pharmacy, Ohio State University, Columbus, OH 43210; Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee, Memphis, TN 38163; and Department of Molecular and Cellular Biochemistry, College of Medicine and Public Health, Ohio State University, Columbus, OH 43210
  • Charles E. Bell
    Division of Pharmaceutics, College of Pharmacy, Ohio State University, Columbus, OH 43210; Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee, Memphis, TN 38163; and Department of Molecular and Cellular Biochemistry, College of Medicine and Public Health, Ohio State University, Columbus, OH 43210
  • James T. Dalton
    Division of Pharmaceutics, College of Pharmacy, Ohio State University, Columbus, OH 43210; Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee, Memphis, TN 38163; and Department of Molecular and Cellular Biochemistry, College of Medicine and Public Health, Ohio State University, Columbus, OH 43210

書誌事項

公開日
2005-04-15
DOI
  • 10.1073/pnas.0500381102
公開者
National Academy of Sciences

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<jats:p> 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 <jats:italic>R</jats:italic> -bicalutamide at 1.8-Å 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 <jats:italic>R</jats:italic> -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 <jats:italic>R</jats:italic> -bicalutamide will provide molecular rationale for the development of new antiandrogens and selective AR modulators. </jats:p>

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