Structural Basis for Antagonism and Resistance of Bicalutamide in Prostate Cancer

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2005 Apr 19

PMID 15833816

Citations 126

Authors

Casey E Bohl

Wenqing Gao

Duane D Miller

Charles E Bell

James T Dalton

Affiliations

Soon will be listed here.

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.

Citing Articles

Study of Glabranin as an Inhibitor Against Prostate Cancer: Molecular Docking, Molecular Dynamics Simulation, MM-PBSA Calculation and QSAR Prediction.

Browne R, Goswami N, Borah P, Roy J Indian J Clin Biochem. 2024; 39(3):331-343.

PMID: 39641116 PMC: 11615236. DOI: 10.1007/s12291-023-01134-3.

Influence of Solvent Polarity on the Conformer Ratio of Bicalutamide in Saturated Solutions: Insights from NOESY NMR Analysis and Quantum-Chemical Calculations.

Sobornova V, Belov K, Krestyaninov M, Khodov I Int J Mol Sci. 2024; 25(15).

PMID: 39125824 PMC: 11311660. DOI: 10.3390/ijms25158254.

A potent new-scaffold androgen receptor antagonist discovered on the basis of a MIEC-SVM model.

Wang X, Chai X, Shan L, Xu X, Xu L, Hou T Acta Pharmacol Sin. 2024; 45(9):1978-1991.

PMID: 38750073 PMC: 11335958. DOI: 10.1038/s41401-024-01284-x.

Efficient Functionalization of Organosulfones via Photoredox Catalysis: Direct Incorporation of -Carbonyl Alkyl Side Chains into -Allyl--Ketosulfones.

Huang H, Li S, Lv Y, Shi Y, Pang T, Zhang R Molecules. 2024; 29(9).

PMID: 38731462 PMC: 11085174. DOI: 10.3390/molecules29091971.

Anti-COVID-19 Potential of Withaferin-A and Caffeic Acid Phenethyl Ester.

Kumar V, Sari A, Gupta D, Ishida Y, Terao K, Kaul S Curr Top Med Chem. 2024; 24(9):830-842.

PMID: 38279743 DOI: 10.2174/0115680266280720231221100004.

References

Matias P, Carrondo M, Coelho R, Thomaz M, Zhao X, Wegg A . Structural basis for the glucocorticoid response in a mutant human androgen receptor (AR(ccr)) derived from an androgen-independent prostate cancer. J Med Chem. 2002; 45(7):1439-46. DOI: 10.1021/jm011072j. View

Marhefka C, Gao W, Chung K, Kim J, He Y, Yin D . Design, synthesis, and biological characterization of metabolically stable selective androgen receptor modulators. J Med Chem. 2004; 47(4):993-8. PMC: 2040239. DOI: 10.1021/jm030336u. View

Mukherjee A, Kirkovsky L, Yao X, YATES R, Miller D, Dalton J . Enantioselective binding of Casodex to the androgen receptor. Xenobiotica. 1996; 26(2):117-22. DOI: 10.3109/00498259609046693. View

Gao W, Kearbey J, Nair V, Chung K, Parlow A, Miller D . Comparison of the pharmacological effects of a novel selective androgen receptor modulator, the 5alpha-reductase inhibitor finasteride, and the antiandrogen hydroxyflutamide in intact rats: new approach for benign prostate hyperplasia. Endocrinology. 2004; 145(12):5420-8. PMC: 2098692. DOI: 10.1210/en.2004-0627. View

Fradet Y . Bicalutamide (Casodex) in the treatment of prostate cancer. Expert Rev Anticancer Ther. 2004; 4(1):37-48. DOI: 10.1586/14737140.4.1.37. View

Kolvenbag G, Blackledge G . Worldwide activity and safety of bicalutamide: a summary review. Urology. 1996; 47(1A Suppl):70-9; discussion 80-4. DOI: 10.1016/s0090-4295(96)80012-4. View

Suzuki H, Akakura K, Komiya A, Aida S, Akimoto S, Shimazaki J . Codon 877 mutation in the androgen receptor gene in advanced prostate cancer: relation to antiandrogen withdrawal syndrome. Prostate. 1996; 29(3):153-8. DOI: 10.1002/1097-0045(199609)29:3<153::aid-pros2990290303>3.0.co;2-5. View

Tucker H, CROOK J, Chesterson G . Nonsteroidal antiandrogens. Synthesis and structure-activity relationships of 3-substituted derivatives of 2-hydroxypropionanilides. J Med Chem. 1988; 31(5):954-9. DOI: 10.1021/jm00400a011. View

Iversen P . Bicalutamide monotherapy for early stage prostate cancer: an update. J Urol. 2003; 170(6 Pt 2):S48-52. DOI: 10.1097/01.ju.0000096491.61731.38. View

10.

Kolvenbag G, Furr B . Relative potency of bicalutamide (Casodex) and flutamide (Eulexin). Urology. 1999; 54(1):194-7. View

11.

He B, Gampe Jr R, Kole A, Hnat A, Stanley T, An G . Structural basis for androgen receptor interdomain and coactivator interactions suggests a transition in nuclear receptor activation function dominance. Mol Cell. 2004; 16(3):425-38. DOI: 10.1016/j.molcel.2004.09.036. View

12.

Akaza H, Yamaguchi A, Matsuda T, Igawa M, Kumon H, Soeda A . Superior anti-tumor efficacy of bicalutamide 80 mg in combination with a luteinizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist monotherapy as first-line treatment for advanced prostate cancer: interim results of a randomized study.... Jpn J Clin Oncol. 2004; 34(1):20-8. DOI: 10.1093/jjco/hyh001. View

13.

Yin D, He Y, Perera M, Hong S, Marhefka C, Stourman N . Key structural features of nonsteroidal ligands for binding and activation of the androgen receptor. Mol Pharmacol. 2002; 63(1):211-23. DOI: 10.1124/mol.63.1.211. View

14.

Chen J, Hwang D, Bohl C, Miller D, Dalton J . A selective androgen receptor modulator for hormonal male contraception. J Pharmacol Exp Ther. 2004; 312(2):546-53. DOI: 10.1124/jpet.104.075424. View

15.

Wirth M, See W, McLeod D, Iversen P, Morris T, Carroll K . Bicalutamide 150 mg in addition to standard care in patients with localized or locally advanced prostate cancer: results from the second analysis of the early prostate cancer program at median followup of 5.4 years. J Urol. 2004; 172(5 Pt 1):1865-70. DOI: 10.1097/01.ju.0000140159.94703.80. View

16.

Hur E, Pfaff S, Payne E, Gron H, Buehrer B, Fletterick R . Recognition and accommodation at the androgen receptor coactivator binding interface. PLoS Biol. 2004; 2(9):E274. PMC: 509409. DOI: 10.1371/journal.pbio.0020274. View

17.

Schellhammer P, Davis J . An evaluation of bicalutamide in the treatment of prostate cancer. Clin Prostate Cancer. 2004; 2(4):213-9. DOI: 10.3816/cgc.2004.n.002. View

18.

Iversen P, Johansson J, Lodding P, Lukkarinen O, Lundmo P, Klarskov P . Bicalutamide (150 mg) versus placebo as immediate therapy alone or as adjuvant to therapy with curative intent for early nonmetastatic prostate cancer: 5.3-year median followup from the Scandinavian Prostate Cancer Group Study Number 6. J Urol. 2004; 172(5 Pt 1):1871-6. DOI: 10.1097/01.ju.0000139719.99825.54. View

19.

Brunger A, Adams P, Clore G, DeLano W, Gros P, Grosse-Kunstleve R . Crystallography & NMR system: A new software suite for macromolecular structure determination. Acta Crystallogr D Biol Crystallogr. 1998; 54(Pt 5):905-21. DOI: 10.1107/s0907444998003254. View

20.

Smith M, Goode M, Zietman A, McGovern F, Lee H, Finkelstein J . Bicalutamide monotherapy versus leuprolide monotherapy for prostate cancer: effects on bone mineral density and body composition. J Clin Oncol. 2004; 22(13):2546-53. DOI: 10.1200/JCO.2004.01.174. View