Structural basis for antagonism and resistance of bicalutamide in prostate cancer

Casey E. Bohl, Wenqing Gao, Duane Miller, Charles E. Bell, James T. Dalton

Research output: Contribution to journalArticle

265 Citations (Scopus)

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-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 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.

Original languageEnglish (US)
Pages (from-to)6201-6206
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number17
DOIs
StatePublished - Apr 26 2005

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Prostatic Neoplasms
Androgen Receptors
Nonsteroidal Anti-Androgens
Androgen Receptor Antagonists
Androgen Antagonists
Dihydrotestosterone
Castration
Gonadotropin-Releasing Hormone
Androgens
Testosterone
bicalutamide
Prostate
X-Rays
Pharmacology
Ligands
Carcinoma
Mutation
Neoplasms
Therapeutics

All Science Journal Classification (ASJC) codes

  • Genetics
  • General

Cite this

Structural basis for antagonism and resistance of bicalutamide in prostate cancer. / Bohl, Casey E.; Gao, Wenqing; Miller, Duane; Bell, Charles E.; Dalton, James T.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 102, No. 17, 26.04.2005, p. 6201-6206.

Research output: Contribution to journalArticle

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AU - Dalton, James T.

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