Targeting alternative sites on the androgen receptor to treat Castration-Resistant Prostate Cancer

International Journal of Molecular Sciences

Volumn 14, Issue 6, 2013, Pages 12496-12519

  Lallous, Nada ^a   Dalal, Kush ^a   Cherkasov, Artem ^a   Rennie, Paul S ^a  

^a UNIVERSITY OF BRITISH COLUMBIA   (Canada)

Author keywords

Androgen receptor; Anti androgens; Castration resistance; Prostate cancer; Protein structure; Structure based drug design

Indexed keywords

1 [3 (2 CHLOROPHENOXY)PROPYL] 1H INDOLE 3 CARBONITRILE; 6 (3,4 DIHYDRO 1H ISOQUINOLIN 2 YL) N (6 METHYLPYRIDIN 2 YL)NICOTINAMIDE; 8 (PROPAN 2 YL) 5,6 DIHYDRO 4H PYRAZINO[3,2,1 JK]CARBAZOLE; ABIRATERONE; ANDROGEN RECEPTOR; ANTIANDROGEN; ARN 509; BICALUTAMIDE; CYCLOPEPTIDE; ENZALUTAMIDE; EPI 001; FLUTAMIDE; GALETERONE; GONADORELIN AGONIST; HYDROXYFLUTAMIDE; KETOCONAZOLE; MEL 3; NILUTAMIDE; NIPHATENONE B ALKYNYL ETHER; ORTERONEL; POLYAMIDE; PROSTATE SPECIFIC ANTIGEN; SHORT HAIRPIN RNA; SINTOKAMIDE; SINTOKAMIDE A; SMALL INTERFERING RNA; UNCLASSIFIED DRUG;

ADVANCED CANCER; AMINO TERMINAL SEQUENCE; ANDROGEN DEPRIVATION THERAPY; BINDING AFFINITY; BINDING SITE; CASTRATION; CASTRATION RESISTANT PROSTATE CANCER; DNA BINDING MOTIF; DRUG EFFICACY; DRUG RECEPTOR BINDING; DRUG TARGETING; EARLY CANCER; ENZYME INHIBITION; HINGE REGION; HORMONE RESPONSIVE ELEMENT; HUMAN; IC 50; NONHUMAN; PROMOTER REGION; PROSTATE CANCER; PROTEIN DOMAIN; PROTEIN FUNCTION; PROTEIN PROTEIN INTERACTION; PROTEIN STRUCTURE; REVIEW; RNA INTERFERENCE; RNA SPLICING; SIGNAL TRANSDUCTION; UNSPECIFIED SIDE EFFECT; ANIMAL; BIOLOGICAL MODEL; CANCER STAGING; CHEMISTRY; MALE; METABOLISM; MOLECULARLY TARGETED THERAPY; PATHOLOGY; PROSTATIC NEOPLASMS, CASTRATION-RESISTANT;

ANIMALS; HUMANS; MALE; MODELS, BIOLOGICAL; MOLECULAR TARGETED THERAPY; NEOPLASM STAGING; PROSTATIC NEOPLASMS, CASTRATION-RESISTANT; RECEPTORS, ANDROGEN; SIGNAL TRANSDUCTION;

EID: 84879127816     PISSN: 16616596     EISSN: 14220067     Source Type: Journal    
DOI: 10.3390/ijms140612496     Document Type: Review

References (130)

1. Siegel, R.; Naishadham, D.; Jemal, A. Cancer statistics, 2013. CA Cancer J. Clin. 2013, 63, 11-30.
2. Green, S.M.; Mostaghel, E.A.; Nelson, P.S. Androgen action and metabolism in prostate cancer. Mol. Cell. Endocrinol. 2012, 360, 3-13.
3. Sampson, N.; Neuwirt, H.; Puhr, M.; Klocker, H.; Eder, I.E. In vitro model systems to study androgen receptor signaling in prostate cancer. Endocr. Relat. Cancer 2013, doi:10.1530/ERC-12-0401.
4. Hiipakka, R.A.; Liao, S. Molecular mechanism of androgen action. Trends Endocrinol. Metab. 1998, 9, 317-324.
5. Jenster, G.; van der Korput, H.A.; van Vroonhoven, C.; van der Kwast, T.H.; Trapman, J.; Brinkmann, A.O. Domains of the human androgen receptor involved in steroid binding, transcriptional activation, and subcellular localization. Mol. Endocrinol. 1991, 5, 1396-1404.
6. Germain, P.; Staels, B.; Dacquet, C.; Spedding, M.; Laudet, V. Overview of nomenclature of nuclear receptors. Pharmacol. Rev. 2006, 58, 685-704.
7. Eick, G.N.; Thornton, J.W. Evolution of steroid receptors from an estrogen-sensitive ancestral receptor. Mol. Cell. Endocrinol. 2011, 334, 31-38.
8. Lamont, K.R.; Tindall, D.J. Androgen regulation of gene expression. Adv. Cancer Res. 2010, 107, 137-162.
9. Saad, F.; Miller, K. Treatment options in castration-resistant prostate cancer: Current therapies and emerging docetaxel-based regimens. Urol. Oncol. 2013, doi:10.1016/j.urolonc.2013.01.005.
10. Lack, N.A.; Axerio-Cilies, P.; Tavassoli, P.; Han, F.Q.; Chan, K.H.; Feau, C.; LeBlanc, E.; Guns, E.T.; Guy, R.K.; Rennie, P.S.; et al. Targeting the binding function 3 (BF3) site of the human androgen receptor through virtual screening. J. Med. Chem. 2011, 54, 8563-8573.
11. Shen, H.C.; Shanmugasundaram, K.; Simon, N.I.; Cai, C.; Wang, H.; Chen, S.; Balk, S.P.; Rigby, A.C. In silico discovery of androgen receptor antagonists with activity in castration resistant prostate cancer. Mol. Endocrinol. 2012, 26, 1836-1846.
12. Song, C.H.; Yang, S.H.; Park, E.; Cho, S.H.; Gong, E.Y.; Khadka, D.B.; Cho, W.J.; Lee, K. Structure-based virtual screening and identification of a novel androgen receptor antagonist. J. Biol. Chem. 2012, 287, 30769-30780.
13. Munuganti, R.S.; Leblanc, E.; Axerio-Cilies, P.; Labriere, C.; Frewin, K.; Singh, K.; Hassona, M.D.; Lack, N.A.; Li, H.; Ban, F.; et al. Targeting the binding function 3 (BF3) site of the androgen receptor through virtual screening. 2. Development of 2-((2-phenoxyethyl) thio)-1H-benzimidazole derivatives. J. Med. Chem. 2013, 56, 1136-1148.
14. Yang, F.; Nickols, N.G.; Li, B.C.; Marinov, G.K.; Said, J.W.; Dervan, P.B. Antitumor activity of a pyrrole-imidazole polyamide. Proc. Natl. Acad. Sci. USA 2013, 110, 1863-1868.
15. Voet, A.; Helsen, C.; Zhang, K.Y.; Claessens, F. The discovery of novel human androgen receptor antagonist chemotypes using a combined pharmacophore screening procedure. Chem. Med. Chem. 2013, 8, 644-651.
16. Caboni, L.; Lloyd, D.G. Beyond the ligand-binding pocket: Targeting alternate sites in nuclear receptors. Med. Res. Rev. 2012, doi:10.1002/med.21275.
17. Mohler, J.L.; Gregory, C.W.; Ford, O.H., 3rd; Kim, D.; Weaver, C.M.; Petrusz, P.; Wilson, E.M.; French, F.S. The androgen axis in recurrent prostate cancer. Clin. Cancer Res. 2004, 10, 440-448.
18. Azzouni, F.; Mohler, J. Biology of castration-recurrent prostate cancer. Urol. Clin. 2012, 39, 435-452.
19. Prescott, J.; Coetzee, G.A. Molecular chaperones throughout the life cycle of the androgen receptor. Cancer Lett. 2006, 231, 12-19.
20. Eichholz, A.; Ferraldeschi, R.; Attard, G.; de Bono, J.S. Putting the brakes on continued androgen receptor signaling in castration-resistant prostate cancer. Mol. Cell. Endocrinol. 2012, 360, 68-75.
21. Centenera, M.M.; Fitzpatrick, A.K.; Tilley, W.D.; Butler, L.M. Hsp90: Still a viable target in prostate cancer. Biochim. Biophys. Acta 2013, 1835, 211-218.
22. Cutress, M.L.; Whitaker, H.C.; Mills, I.G.; Stewart, M.; Neal, D.E. Structural basis for the nuclear import of the human androgen receptor. J. Cell Sci. 2008, 121, 957-968.
23. Kaku, N.; Matsuda, K.; Tsujimura, A.; Kawata, M. Characterization of nuclear import of the domain-specific androgen receptor in association with the importin alpha/beta and Ran-guanosine 5'-triphosphate systems. Endocrinology. 2008, 149, 3960-3969.
24. Van Royen, M.E.; van Cappellen, W.A.; de Vos, C.; Houtsmuller, A.B.; Trapman, J. Stepwise androgen receptor dimerization. J. Cell Sci. 2012, 125, 1970-1979.
25. Heinlein, C.A.; Chang, C. Androgen receptor in prostate cancer. Endocr. Rev. 2004, 25, 276-308.
26. Van der Sluis, T.M.; van Moorselaar, R.J.; Meuleman, E.J.; Ter Haar, R.W.; Bui, H.N.; Heijboer, A.C.; Vis, A.N. Relationship between body mass index and serum testosterone Concentration in patients receiving luteinizing hormone-releasing hormone agonist therapy for prostate cancer. Urology 2013, 81, 1005-1009.
27. Tammela, T.L. Endocrine prevention and treatment of prostate cancer. Mol. Cell. Endocrinol. 2012, 360, 59-67.
28. Liu, S.V.; Liu, S.; Pinski, J. Luteinizing hormone-releasing hormone receptor targeted agents for prostate cancer. Expert Opin. Investig. Drugs 2011, 20, 769-778.
29. Friedlander, T.W.; Ryan, C.J. Targeting the androgen receptor. Urol. Clin. 2012, 39, 453-464.
30. Sadar, M.D. Advances in small molecule inhibitors of androgen receptor for the treatment of advanced prostate cancer. World J. Urol. 2012, 30, 311-318.
31. Ferraldeschi, R.; de Bono, J. Agents that target androgen synthesis in castration-resistant prostate cancer. Cancer J. 2013, 19, 34-42.
32. Lim, A.C.; Attard, G. Improved therapeutic targeting of the androgen receptor: Rational drug design improves survival in castration-resistant prostate cancer. Curr. Drug Targets 2013, 14, 408-419.
33. Pont, A.; Williams, P.L.; Azhar, S.; Reitz, R.E.; Bochra, C.; Smith, E.R.; Stevens, D.A. Ketoconazole blocks testosterone synthesis. Arch. Intern. Med. 1982, 142, 2137-2140.
34. Lamberts, S.W.; Bons, E.G.; Bruining, H.A.; de Jong, F.H. Differential effects of the imidazole derivatives etomidate, ketoconazole and miconazole and of metyrapone on the secretion of cortisol and its precursors by human adrenocortical cells. J. Pharmacol. Exp. Ther. 1987, 240, 259-264.
35. Fizazi, K.; Scher, H.I.; Molina, A.; Logothetis, C.J.; Chi, K.N.; Jones, R.J.; Staffurth, J.N.; North, S.; Vogelzang, N.J.; Saad, F.; et al. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: Final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2012, 13, 983-992.
36. Zhu, H.; Garcia, J.A. Targeting the adrenal gland in castration-resistant prostate cancer: A case for orteronel, a selective CYP-17 17, 20-lyase inhibitor. Curr. Oncol. Rep. 2013, 15, 105-112.
37. Bruno, R.D.; Gover, T.D.; Burger, A.M.; Brodie, A.M.; Njar, V.C. 17alpha-Hydroxylase/17, 20 lyase inhibitor VN/124-1 inhibits growth of androgen-independent prostate cancer cells via induction of the endoplasmic reticulum stress response. Mol. Cancer Ther. 2008, 7, 2828-2836.
38. Ferraldeschi, R.; Sharifi, N.; Auchus, R.J.; Attard, G. Molecular pathways: Inhibiting steroid biosynthesis in prostate cancer. Clin. Cancer Res. 2013, doi:10.1158/1078-0432.CCR-12-0931.
39. Tran, C.; Ouk, S.; Clegg, N.J.; Chen, Y.; Watson, P.A.; Arora, V.; Wongvipat, J.; Smith-Jones, P.M.; Yoo, D.; Kwon, A.; et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science 2009, 324, 787-790.
40. Schweizer, M.T.; Antonarakis, E.S. Abiraterone and other novel androgen-directed strategies for the treatment of prostate cancer: A new era of hormonal therapies is born. Ther. Adv. Urol. 2012, 4, 167-178.
41. Rathkopf, D.; Scher, H.I. Androgen receptor antagonists in castration-resistant prostate cancer. Cancer J. 2013, 19, 43-49.
42. Liao, X.; Tang, S.; Thrasher, J.B.; Griebling, T.L.; Li, B. Small-interfering RNA-induced androgen receptor silencing leads to apoptotic cell death in prostate cancer. Mol. Cancer. Ther. 2005, 4, 505-515.
43. Cheng, H.; Snoek, R.; Ghaidi, F.; Cox, M.E.; Rennie, P.S. Short hairpin RNA knockdown of the androgen receptor attenuates ligand-independent activation and delays tumor progression. Cancer Res. 2006, 66, 10613-10620.
44. Snoek, R.; Cheng, H.; Margiotti, K.; Wafa, L.A.; Wong, C.A.; Wong, E.C.; Fazli, L.; Nelson, C.C.; Gleave, M.E.; Rennie, P.S. In vivo knockdown of the androgen receptor results in growth inhibition and regression of well-established, castration-resistant prostate tumors. Clin. Cancer Res. 2009, 15, 39-47.
45. Lee, J.B.; Zhang, K.; Tam, Y.Y.; Tam, Y.K.; Belliveau, N.M.; Sung, V.Y.; Lin, P.J.; LeBlanc, E.; Ciufolini, M.A.; Rennie, P.S.; et al. Lipid nanoparticle sirna systems for silencing the androgen receptor in human prostate cancer in vivo. Int. J. Cancer 2012, 131, E781-790.
46. Sternberg, C.N.; Petrylak, D.P.; Sartor, O.; Witjes, J.A.; Demkow, T.; Ferrero, J.M.; Eymard, J.C.; Falcon, S.; Calabro, F.; James, N.; et al. Multinational, double-blind, phase iii study of prednisone and either satraplatin or placebo in patients with castrate-refractory prostate cancer progressing after prior chemotherapy: The sparc trial. J. Clin. Oncol. 2009, 27, 5431-5438.
47. Molina, A.; Belldegrun, A. Novel therapeutic strategies for castration resistant prostate cancer: Inhibition of persistent androgen production and androgen receptor mediated signaling. J. Urol. 2011, 185, 787-794.
48. Cheng, H.H.; Lin, D.W.; Yu, E.Y. Advanced clinical states in prostate cancer. Urol. Clin. 2012, 39, 561-571.
49. Loriot, Y.; Zoubeidi, A.; Gleave, M.E. Targeted therapies in metastatic castration-resistant prostate cancer: Beyond the androgen receptor. Urol. Clin. 2012, 39, 517-531.
50. Chen, C.D.; Welsbie, D.S.; Tran, C.; Baek, S.H.; Chen, R.; Vessella, R.; Rosenfeld, M.G.; Sawyers, C.L. Molecular determinants of resistance to antiandrogen therapy. Nat. Med. 2004, 10, 33-39.
51. Taplin, M.E.; Bubley, G.J.; Shuster, T.D.; Frantz, M.E.; Spooner, A.E.; Ogata, G.K.; Keer, H.N.; Balk, S.P. Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer. N. Engl. J. Med. 1995, 332, 1393-1398.
52. Stanbrough, M.; Bubley, G.J.; Ross, K.; Golub, T.R.; Rubin, M.A.; Penning, T.M.; Febbo, P.G.; Balk, S.P. Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res. 2006, 66, 2815-2825.
53. Montgomery, R.B.; Mostaghel, E.A.; Vessella, R.; Hess, D.L.; Kalhorn, T.F.; Higano, C.S.; True, L.D.; Nelson, P.S. Maintenance of intratumoral androgens in metastatic prostate cancer: A mechanism for castration-resistant tumor growth. Cancer Res. 2008, 68, 4447-4454.
54. Nyquist, M.D.; Dehm, S.M. Interplay between genomic alterations and androgen receptor signaling during prostate cancer development and progression. Horm. Cancer 2013, 4, 61-69.
55. Watson, P.A.; Chen, Y.F.; Balbas, M.D.; Wongvipat, J.; Socci, N.D.; Viale, A.; Kim, K.; Sawyers, C.L. Constitutively active androgen receptor splice variants expressed in castration-resistant prostate cancer require full-length androgen receptor. Proc. Natl. Acad. Sci. USA 2010, 107, 16759-16765.
56. Brand, L.J.; Dehm, S.M. Androgen receptor gene rearrangements: New perspectives on prostate cancer progression. Curr. Drug Targets 2013, 14, 441-449.
57. Dehm, S.M.; Tindall, D.J. Alternatively spliced androgen receptor variants. Endocr. Relat. Cancer 2011, 18, R183-196.
58. Li, Y.; Chan, S.C.; Brand, L.J.; Hwang, T.H.; Silverstein, K.A.; Dehm, S.M. Androgen receptor splice variants mediate enzalutamide resistance in castration-resistant prostate cancer cell lines. Cancer Res. 2013, 73, 483-489.
59. Cao, B.; Liu, X.; Li, J.; Liu, S.; Qi, Y.; Xiong, Z.; Zhang, A.; Wiese, T.; Fu, X.; Gu, J.; et al. 20(S)-protopanaxadiol-aglycone downregulation of the full-length and splice variants of androgen receptor. Int. J. Cancer 2013, 132, 1277-1287.
60. Lamont, K.R.; Tindall, D.J. Minireview: Alternative activation pathways for the androgen receptor in prostate cancer. Mol. Endocrinol. 2011, 25, 897-907.
61. Rice, P.; Longden, I.; Bleasby, A. Emboss: The european molecular biology open software suite. Trends Genet. 2000, 16, 276-277.
62. Robins, D.M.; Albertelli, M.A.; O'Mahony, O.A. Androgen receptor variants and prostate cancer in humanized AR mice. J. Steroid Biochem. 2008, 108, 230-236.
63. La Spada, A.R.; Wilson, E.M.; Lubahn, D.B.; Harding, A.E.; Fischbeck, K.H. Androgen receptor gene mutations in x-linked spinal and bulbar muscular atrophy. Nature 1991, 352, 77-79.
64. Choong, C.S.; Kemppainen, J.A.; Wilson, E.M. Evolution of the primate androgen receptor: A structural basis for disease. J. Mol. Evol. 1998, 47, 334-342.
65. Davies, P.; Watt, K.; Kelly, S.M.; Clark, C.; Price, N.C.; McEwan, I.J. Consequences of poly-glutamine repeat length for the conformation and folding of the androgen receptor amino-terminal domain. J. Mol. Endocrinol. 2008, 41, 301-314.
66. Betney, R.; McEwan, I.J. Role of conserved hydrophobic amino acids in androgen receptor AF-1 function. J. Mol. Endocrinol. 2003, 31, 427-439.
67. Jenster, G.; van der Korput, H.A.; Trapman, J.; Brinkmann, A.O. Identification of two transcription activation units in the N-terminal domain of the human androgen receptor. J. Biol. Chem. 1995, 270, 7341-7346.
68. Reid, J.; Betney, R.; Watt, K.; McEwan, I.J. The androgen receptor transactivation domain: The interplay between protein conformation and protein-protein interactions. Biochem. Soc. Trans. 2003, 31, 1042-1046.
69. He, B.; Kemppainen, J.A.; Wilson, E.M. FXXLF and WXXLF sequences mediate the NH2-terminal interaction with the ligand binding domain of the androgen receptor. J. Biol. Chem. 2000, 275, 22986-22994.
70. He, B.; Wilson, E.M. The NH(2)-terminal and carboxyl-terminal interaction in the human androgen receptor. Mol. Genet. Metab. 2002, 75, 293-298.
71. McEwan, I.J. Molecular mechanisms of androgen receptor-mediated gene regulation: Structure-function analysis of the AF-1 domain. Endocr. Relat. Cancer 2004, 11, 281-293.
72. McEwan, I.J. Intrinsic disorder in the androgen receptor: Identification, characterisation and drugability. Mol. Biosyst. 2012, 8, 82-90.
73. McEwan, I.J.; Gustafsson, J. Interaction of the human androgen receptor transactivation function with the general transcription factor TFIIF. Proc. Natl. Acad. Sci. USA 1997, 94, 8485-8490.
74. Reid, J.; Murray, I.; Watt, K.; Betney, R.; McEwan, I.J. The androgen receptor interacts with multiple regions of the large subunit of general transcription factor TFIIF. J. Biol. Chem. 2002, 277, 41247-41253.
75. Lee, D.K.; Duan, H.O.; Chang, C. From androgen receptor to the general transcription factor tfiih. Identification of cdk activating kinase (CAK) as an androgen receptor NH(2)-terminal associated coactivator. J. Biol. Chem. 2000, 275, 9308-9313.
76. Fronsdal, K.; Engedal, N.; Slagsvold, T.; Saatcioglu, F. CREB binding protein is a coactivator for the androgen receptor and mediates cross-talk with AP-1. J. Biol. Chem. 1998, 273, 31853-31859.
77. Aarnisalo, P.; Palvimo, J.J.; Janne, O.A. CREB-binding protein in androgen receptor-mediated signaling. Proc. Natl. Acad. Sci. USA 1998, 95, 2122-2127.
78. Dotzlaw, H.; Moehren, U.; Mink, S.; Cato, A.C.; Iniguez Lluhi, J.A.; Baniahmad, A. The amino terminus of the human AR is target for corepressor action and antihormone agonism. Mol. Endocrinol. 2002, 16, 661-673.
79. Umesono, K.; Evans, R.M. Determinants of target gene specificity for steroid/thyroid hormone receptors. Cell 1989, 57, 1139-1146.
80. Claessens, F.; Alen, P.; Devos, A.; Peeters, B.; Verhoeven, G.; Rombauts, W. The androgen-specific probasin response element 2 interacts differentially with androgen and glucocorticoid receptors. J. Biol. Chem. 1996, 271, 19013-19016.
81. Schoenmakers, E.; Alen, P.; Verrijdt, G.; Peeters, B.; Verhoeven, G.; Rombauts, W.; Claessens, F. Differential DNA binding by the androgen and glucocorticoid receptors involves the second Zn-finger and a C-terminal extension of the DNA-binding domains. Biochem. J. 1999, 341, 515-521.
82. Denayer, S.; Helsen, C.; Thorrez, L.; Haelens, A.; Claessens, F. The rules of DNA recognition by the androgen receptor. Mol. Endocrinol. 2010, 24, 898-913.
83. Shaffer, P.L.; Jivan, A.; Dollins, D.E.; Claessens, F.; Gewirth, D.T. Structural basis of androgen receptor binding to selective androgen response elements. Proc. Natl. Acad. Sci. USA 2004, 101, 4758-4763.
84. Zhou, Z.X.; Sar, M.; Simental, J.A.; Lane, M.V.; Wilson, E.M. A ligand-dependent bipartite nuclear targeting signal in the human androgen receptor. Requirement for the DNA-binding domain and modulation by NH2-terminal and carboxyl-terminal sequences. J. Biol. Chem. 1994, 269, 13115-13123.
85. Jenster, G.; Trapman, J.; Brinkmann, A.O. Nuclear import of the human androgen receptor. Biochem. J. 1993, 293, 761-768.
86. Clinckemalie, L.; Vanderschueren, D.; Boonen, S.; Claessens, F. The hinge region in androgen receptor control. Mol. Cell. Endocrinol. 2012, 358, 1-8.
87. Simental, J.A.; Sar, M.; Lane, M.V.; French, F.S.; Wilson, E.M. Transcriptional activation and nuclear targeting signals of the human androgen receptor. J. Biol. Chem. 1991, 266, 510-518.
88. Pereira de Jesus-Tran, K.; Cote, P.L.; Cantin, L.; Blanchet, J.; Labrie, F.; Breton, R. Comparison of crystal structures of human androgen receptor ligand-binding domain complexed with various agonists reveals molecular determinants responsible for binding affinity. Protein Sci. 2006, 15, 987-999.
89. He, B.; Gampe, R.T., Jr.; Kole, A.J.; Hnat, A.T.; Stanley, T.B.; An, G.; Stewart, E.L.; Kalman, R.I.; Minges, J.T.; Wilson, E.M. Structural basis for androgen receptor interdomain and coactivator interactions suggests a transition in nuclear receptor activation function dominance. Mol. Cell 2004, 16, 425-438.
90. Gao, W.; Bohl, C.E.; Dalton, J.T. Chemistry and structural biology of androgen receptor. Chem. Rev. 2005, 105, 3352-3370.
91. Zhou, X.E.; Suino-Powell, K.M.; Li, J.; He, Y.; Mackeigan, J.P.; Melcher, K.; Yong, E.L.; Xu, H.E. Identification of SRC3/AIB1 as a preferred coactivator for hormone-activated androgen receptor. J. Biol. Chem. 2010, 285, 9161-9171.
92. Wilson, E.M. Analysis of interdomain interactions of the androgen receptor. Methods Mol. Biol. 2011, 776, 113-129.
93. Estebanez-Perpina, E.; Arnold, L.A.; Nguyen, P.; Rodrigues, E.D.; Mar, E.; Bateman, R.; Pallai, P.; Shokat, K.M.; Baxter, J.D.; Guy, R.K.; et al. A surface on the androgen receptor that allosterically regulates coactivator binding. Proc. Natl. Acad. Sci. USA 2007, 104, 16074-16079.
94. Grosdidier, S.; Carbo, L.R.; Buzon, V.; Brooke, G.; Nguyen, P.; Baxter, J.D.; Bevan, C.; Webb, P.; Estebanez-Perpina, E.; Fernandez-Recio, J. Allosteric conversation in the androgen receptor ligand-binding domain surfaces. Mol. Endocrinol. 2012, 26, 1078-1090.
95. De Leon, J.T.; Iwai, A.; Feau, C.; Garcia, Y.; Balsiger, H.A.; Storer, C.L.; Suro, R.M.; Garza, K.M.; Lee, S.; Kim, Y.S.; et al. Targeting the regulation of androgen receptor signaling by the heat shock protein 90 cochaperone FKBP52 in prostate cancer cells. Proc. Natl. Acad. Sci. USA 2011, 108, 11878-11883.
96. Gottlieb, B.; Beitel, L.K.; Nadarajah, A.; Paliouras, M.; Trifiro, M. The androgen receptor gene mutations database: 2012 update. Hum. Mutat. 2012, 33, 887-894.
97. Guo, Z.; Qiu, Y. A new trick of an old molecule: Androgen receptor splice variants taking the stage?! Int. J. Biol. Sci. 2011, 7, 815-822.
98. Ahrens-Fath, I.; Politz, O.; Geserick, C.; Haendler, B. Androgen receptor function is modulated by the tissue-specific AR45 variant. FEBS J. 2005, 272, 74-84.
99. Guo, Z.; Yang, X.; Sun, F.; Jiang, R.; Linn, D.E.; Chen, H.; Kong, X.; Melamed, J.; Tepper, C.G.; Kung, H.J.; et al. A novel androgen receptor splice variant is up-regulated during prostate cancer progression and promotes androgen depletion-resistant growth. Cancer Res. 2009, 69, 2305-2313.
100. Sun, S.; Sprenger, C.C.; Vessella, R.L.; Haugk, K.; Soriano, K.; Mostaghel, E.A.; Page, S.T.; Coleman, I.M.; Nguyen, H.M.; Sun, H.; et al. Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant. J. Clin. Invest. 2010, 120, 2715-2730.
101. Hu, R.; Dunn, T.A.; Wei, S.; Isharwal, S.; Veltri, R.W.; Humphreys, E.; Han, M.; Partin, A.W.; Vessella, R.L.; Isaacs, W.B.; et al. Ligand-independent androgen receptor variants derived from splicing of cryptic exons signify hormone-refractory prostate cancer. Cancer Res. 2009, 69, 16-22.
102. Dehm, S.M.; Schmidt, L.J.; Heemers, H.V.; Vessella, R.L.; Tindall, D.J. Splicing of a novel androgen receptor exon generates a constitutively active androgen receptor that mediates prostate cancer therapy resistance. Cancer Res. 2008, 68, 5469-5477.
103. Suzuki, H.; Sato, N.; Watabe, Y.; Masai, M.; Seino, S.; Shimazaki, J. Androgen receptor gene mutations in human prostate cancer. J. Steroid Biochem. 1993, 46, 759-765.
104. Bohl, C.E.; Gao, W.; Miller, D.D.; Bell, C.E.; Dalton, J.T. Structural basis for antagonism and resistance of bicalutamide in prostate cancer. Proc. Natl. Acad. Sci. USA 2005, 102, 6201-6206.
105. Bohl, C.E.; Miller, D.D.; Chen, J.; Bell, C.E.; Dalton, J.T. Structural basis for accommodation of nonsteroidal ligands in the androgen receptor. J. Biol. Chem. 2005, 280, 37747-37754.
106. Salvati, M.E.; Balog, A.; Shan, W.; Wei, D.D.; Pickering, D.; Attar, R.M.; Geng, J.; Rizzo, C.A.; Gottardis, M.M.; Weinmann, R.; et al. Structure based approach to the design of bicyclic-1H-isoindole-1, 3(2H)-dione based androgen receptor antagonists. Bioorg. Med. Chem. Lett. 2005, 15, 271-276.
107. Duke, C.B.; Jones, A.; Bohl, C.E.; Dalton, J.T.; Miller, D.D. Unexpected binding orientation of bulky-B-ring anti-androgens and implications for future drug targets. J. Med. Chem. 2011, 54, 3973-3976.
108. Shiau, A.K.; Barstad, D.; Loria, P.M.; Cheng, L.; Kushner, P.J.; Agard, D.A.; Greene, G.L. The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell 1998, 95, 927-937.
109. Brzozowski, A.M.; Pike, A.C.; Dauter, Z.; Hubbard, R.E.; Bonn, T.; Engstrom, O.; Ohman, L.; Greene, G.L.; Gustafsson, J.A.; Carlquist, M. Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 1997, 389, 753-758.
110. Kauppi, B.; Jakob, C.; Farnegardh, M.; Yang, J.; Ahola, H.; Alarcon, M.; Calles, K.; Engstrom, O.; Harlan, J.; Muchmore, S.; et al. The three-dimensional structures of antagonistic and agonistic forms of the glucocorticoid receptor ligand-binding domain: Ru-486 induces a transconformation that leads to active antagonism. J. Biol. Chem. 2003, 278, 22748-22754.
111. Pal, S.K.; Stein, C.A.; Sartor, O. Enzalutamide for the treatment of prostate cancer. Expert Opin. Pharmacother. 2013, 14, 679-685.
112. Scher, H.I.; Beer, T.M.; Higano, C.S.; Anand, A.; Taplin, M.E.; Efstathiou, E.; Rathkopf, D.; Shelkey, J.; Yu, E.Y.; Alumkal, J.; et al. Antitumour activity of MDV3100 in castration-resistant prostate cancer: A phase 1-2 study. Lancet 2010, 375, 1437-1446.
113. Nique, F.; Hebbe, S.; Peixoto, C.; Annoot, D.; Lefrancois, J.M.; Duval, E.; Michoux, L.; Triballeau, N.; Lemoullec, J.M.; Mollat, P.; et al. Discovery of diarylhydantoins as new selective androgen receptor modulators. J. Med. Chem. 2012, 55, 8225-8235.
114. Clegg, N.J.; Wongvipat, J.; Joseph, J.D.; Tran, C.; Ouk, S.; Dilhas, A.; Chen, Y.; Grillot, K.; Bischoff, E.D.; Cai, L.; et al. ARN-509: A novel antiandrogen for prostate cancer treatment. Cancer Res. 2012, 72, 1494-1503.
115. Yang, S.H.; Song, C.H.; van, H.T.; Park, E.; Khadka, D.B.; Gong, E.Y.; Lee, K.; Cho, W.J. SAR based design of nicotinamides as a novel class of androgen receptor antagonists for prostate cancer. J. Med. Chem. 2013, 56, 3414-3418.
116. Helsen, C.; Marchand, A.; Chaltin, P.; Munck, S.; Voet, A.; Verstuyf, A.; Claessens, F. Identification and characterization of MEL-3, a novel ar antagonist that suppresses prostate cancer cell growth. Mol. Cancer Ther. 2012, 11, 1257-1268.
117. Buzon, V.; Carbo, L.R.; Estruch, S.B.; Fletterick, R.J.; Estebanez-Perpina, E. A conserved surface on the ligand binding domain of nuclear receptors for allosteric control. Mol. Cell. Endocrinol. 2012, 348, 394-402.
118. Axerio-Cilies, P.; Lack, N.A.; Nayana, M.R.; Chan, K.H.; Yeung, A.; Leblanc, E.; Guns, E.S.; Rennie, P.S.; Cherkasov, A. Inhibitors of androgen receptor activation function-2 (AF2) site identified through virtual screening. J. Med. Chem. 2011, 54, 6197-6205.
119. Sadar, M.D. Small molecule inhibitors targeting the "achilles' heel" of androgen receptor activity. Cancer Res. 2011, 71, 1208-1213.
120. Sadar, M.D.; Williams, D.E.; Mawji, N.R.; Patrick, B.O.; Wikanta, T.; Chasanah, E.; Irianto, H.E.; Soest, R.V.; Andersen, R.J. Sintokamides A to E, chlorinated peptides from the sponge Dysidea sp. That inhibit transactivation of the N-terminus of the androgen receptor in prostate cancer cells. Org. Lett. 2008, 10, 4947-4950.
121. Meimetis, L.G.; Williams, D.E.; Mawji, N.R.; Banuelos, C.A.; Lal, A.A.; Park, J.J.; Tien, A.H.; Fernandez, J.G.; de Voogd, N.J.; Sadar, M.D.; et al. Niphatenones, glycerol ethers from the sponge niphates digitalis block androgen receptor transcriptional activity in prostate cancer cells: Structure elucidation, synthesis, and biological activity. J. Med. Chem. 2012, 55, 503-514.
122. Quayle, S.N.; Mawji, N.R.; Wang, J.; Sadar, M.D. Androgen receptor decoy molecules block the growth of prostate cancer. Proc. Natl. Acad. Sci. USA 2007, 104, 1331-1336.
123. Van de Wijngaart, D.J.; Dubbink, H.J.; van Royen, M.E.; Trapman, J.; Jenster, G. Androgen receptor coregulators: Recruitment via the coactivator binding groove. Mol. Cell. Endocrinol. 2012, 352, 57-69.
124. Van de Wijngaart, D.J.; van Royen, M.E.; Hersmus, R.; Pike, A.C.; Houtsmuller, A.B.; Jenster, G.; Trapman, J.; Dubbink, H.J. Novel FXXFF and FXXMF motifs in androgen receptor cofactors mediate high affinity and specific interactions with the ligand-binding domain. J. Biol. Chem. 2006, 281, 19407-19416.
125. Van Royen, M.E.; Cunha, S.M.; Brink, M.C.; Mattern, K.A.; Nigg, A.L.; Dubbink, H.J.; Verschure, P.J.; Trapman, J.; Houtsmuller, A.B. Compartmentalization of androgen receptor protein-protein interactions in living cells. J. Cell Biol. 2007, 177, 63-72.
126. Andersen, R.J.; Mawji, N.R.; Wang, J.; Wang, G.; Haile, S.; Myung, J.K.; Watt, K.; Tam, T.; Yang, Y.C.; Banuelos, C.A.; et al. Regression of castrate-recurrent prostate cancer by a small-molecule inhibitor of the amino-terminus domain of the androgen receptor. Cancer Cell 2010, 17, 535-546.
127. Cherian, M.T.; Wilson, E.M.; Shapiro, D.J. A competitive inhibitor that reduces recruitment of androgen receptor to androgen-responsive genes. J. Biol. Chem. 2012, 287, 23368-23380.
128. Chenoweth, D.M.; Dervan, P.B. Structural basis for cyclic Py-Im polyamide allosteric inhibition of nuclear receptor binding. J. Am. Chem. Soc. 2010, 132, 14521-14529.
129. Nickols, N.G.; Dervan, P.B. Suppression of androgen receptor-mediated gene expression by a sequence-specific DNA-binding polyamide. Proc. Natl. Acad. Sci. USA 2007, 104, 10418-10423.
130. Chenoweth, D.M.; Dervan, P.B. Allosteric modulation of DNA by small molecules. Proc. Natl. Acad. Sci. USA 2009, 106, 13175-13179.