World Journal of Urology

, Volume 30, Issue 3, pp 311–318 | Cite as

Advances in small molecule inhibitors of androgen receptor for the treatment of advanced prostate cancer

  • Marianne D. SadarEmail author
Topic Paper



Current treatments for localized prostate cancer include brachytherapy, external beam radiation, surgery, and active surveillance. Unfortunately, 20–40% of prostate cancer patients will experience recurrence and require hormonal therapies. These therapies involve androgen ablation by chemical or surgical castration and application of antiandrogens. Hormonal therapy is initially effective, but will inevitably fail and the disease will progress to lethal castration-resistant prostate cancer (CRPC) from which patients succumb within 2 years. CRPC is considered to be dependent on transcriptionally active androgen receptors (AR). This article reviews recent advances in the discovery and development of small molecule inhibitors of AR.


A PubMed database search was performed for articles focused on small molecule inhibitors of AR for potential development for the treatment of prostate cancer. Compounds with broad effects on other pathways were not included.


Currently, there are several novel antiandrogens being tested in the clinic that have improved affinity for the AR and work by different mechanisms to the current battery of approved antiandrogens that are discussed. Small molecule inhibitors that interact with regions other than the AR ligand-binding pocket have been also been discovered. These small molecules include allosteric inhibitors of the LBD, compounds that alter AR conformation, and antagonists to the AR NTD and are highlighted.


CRPC is dependent upon transcriptionally active AR. Survival improvement may be achieved by complete blockade of all AR activity using novel small molecule inhibitors with unique mechanisms of action.


Castration-resistant prostate cancer Androgen receptor Small molecules Antagonist Allosteric inhibitor Intrinsically disordered Antiandrogens EPI-001 



This work was supported by grants from the Canadian Institutes of Health Research (MOP-79308, PPP-102189) and the US National Cancer Institute (2R01 CA105304).

Conflict of interest

MDS receives compensation from ESSA Pharma Inc.


  1. 1.
    Poujol N, Wurtz JM, Tahiri B, Lumbroso S, Nicolas JC, Moras D, Sultan C (2000) Specific recognition of androgens by their nuclear receptor. A structure-function study. J Biol Chem 275:24022–24031PubMedCrossRefGoogle Scholar
  2. 2.
    Montgomery RB, Mostaghel EA, Vessella R, Hess DL, Kalhorn TF, Higano CS, True LD, Nelson PS (2008) Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res 68:4447–4454PubMedCrossRefGoogle Scholar
  3. 3.
    de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, Chi KN, Jones RJ, Goodman OB Jr, Saad F, Staffurth JN, Mainwaring P, Harland S, Flaig TW, Hutson TE, Cheng T, Patterson H, Hainsworth JD, Ryan CJ, Sternberg CN, Ellard SL, Fléchon A, Saleh M, Scholz M, Efstathiou E, Zivi A, Bianchini D, Loriot Y, Chieffo N, Kheoh T, Haqq CM, Scher HI, COU-AA-301 Investigators (2011) Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 364:1995–2005PubMedCrossRefGoogle Scholar
  4. 4.
    Bruno RD, Gover TD, Burger AM, Brodie AM, Njar VC (2008) 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 7:2828–2836PubMedCrossRefGoogle Scholar
  5. 5.
    Vasaitis T, Belosay A, Schayowitz A, Khandelwal A, Chopra P, Gediya LK, Guo Z, Fang HB, Njar VC, Brodie AM (2008) Androgen receptor inactivation contributes to antitumor efficacy of 17{alpha}-hydroxylase/17, 20-lyase inhibitor 3beta-hydroxy-17-(1H-benzimidazole-1-yl) androsta-5,16-diene in prostate cancer. Mol Cancer Ther 7:2348–2357PubMedCrossRefGoogle Scholar
  6. 6.
    Waller AS, Sharrard RM, Berthon P, Maitland NJ (2000) Androgen receptor localisation and turnover in human prostate epithelium treated with the antiandrogen, casodex. J Mol Endocrinol 24:339–351PubMedCrossRefGoogle Scholar
  7. 7.
    Neri RO, Monahan MD, Meyer JG, Afonso BA, Tabachnick IA (1967) Biological studies on an anti-androgen (SH 714). Eur J Pharmacol 1:438–444PubMedCrossRefGoogle Scholar
  8. 8.
    Moguilewsky M, Fiet J, Tournemine C, Raynaud JP (1986) Pharmacology of an antiandrogen, anandron, used as an adjuvant therapy in the treatment of prostate cancer. J Steroid Biochem 24:139–146PubMedCrossRefGoogle Scholar
  9. 9.
    Furr BJ, Valcaccia B, Curry B, Woodburn JR, Chesterson G, Tucker H (1987) ICI 176, 334: a novel non-steroidal, peripherally selective antiandrogen. J Endocrinol 113:R7–R9PubMedCrossRefGoogle Scholar
  10. 10.
    Kolvenbag GJ, Blackledge GR, Gotting-Smith K (1998) Bicalutamide (Casodex) in the treatment of prostate cancer: history of clinical development. Prostate 34:61–72PubMedCrossRefGoogle Scholar
  11. 11.
    Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V, Wongvipat J, Smith-Jones PM, Yoo D, Kwon A, Wasielewska T, Welsbie D, Chen CD, Higano CS, Beer TM, Hung DT, Scher HI, Jung ME, Sawyers CL (2009) Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science 324:787–790PubMedCrossRefGoogle Scholar
  12. 12.
    Yoshida T, Kinoshita H, Segawa T, Nakamura E, Inoue T, Shimizu Y, Kamoto T, Ogawa O (2005) Antiandrogen bicalutamide promotes tumor growth in a novel androgen-dependent prostate cancer xenograft model derived from a bicalutamide-treated patient. Cancer Res 65:9611–9616PubMedCrossRefGoogle Scholar
  13. 13.
    Scher HI, Beer TM, Higano CS, Anand A, Taplin ME, Efstathiou E, Rathkopf D, Shelkey J, Yu EY, Alumkal J, Hung D, Hirmand M, Seely L, Morris MJ, Danila DC, Humm J, Larson S, Fleisher M, Sawyers CL, Prostate Cancer Foundation/Department of Defense Prostate Cancer Clinical Trials Consortium (2010) Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1–2 study. Lancet 375:1437–1446PubMedCrossRefGoogle Scholar
  14. 14.
    Attar RM, Jure-Kunkel M, Balog A, Cvijic ME, Dell-John J, Rizzo CA, Schweizer L, Spires TE, Platero JS, Obermeier M, Shan W, Salvati ME, Foster WR, Dinchuk J, Chen SJ, Vite G, Kramer R, Gottardis MM (2009) Discovery of BMS-641988, a novel and potent inhibitor of androgen receptor signaling for the treatment of prostate cancer. Cancer Res 69:6522–6530PubMedCrossRefGoogle Scholar
  15. 15.
    Rathkopf D, Liu G, Carducci MA, Eisenberger MA, Anand A, Morris MJ, Slovin SF, Sasaki Y, Takahashi S, Ozono S, Fung NK, Cheng S, Gan J, Gottardis M, Obermeier MT, Reddy J, Zhang S, Vakkalagadda BJ, Alland L, Wilding G, Scher HI, Prostate Cancer Clinical Trials Consortium (2011) Phase I dose-escalation study of the novel antiandrogen BMS-641988 in patients with castration-resistant prostate cancer. Clin Cancer Res 17:880–887PubMedCrossRefGoogle Scholar
  16. 16.
    Estébanez-Perpiñá E, Arnold LA, Nguyen P, Rodrigues ED, Mar E, Bateman R, Pallai P, Shokat KM, Baxter JD, Guy RK, Webb P, Fletterick RJ (2007) A surface on the androgen receptor that allosterically regulates coactivator binding. Proc Natl Acad Sci USA 104:16074–16079PubMedCrossRefGoogle Scholar
  17. 17.
    Nishimura K, Ting HJ, Harada Y, Tokizane T, Nonomura N, Kang HY, Chang HC, Yeh S, Miyamoto H, Shin M, Aozasa K, Okuyama A, Chang C (2003) Modulation of androgen receptor transactivation by gelsolin: a newly identified androgen receptor coregulator. Cancer Res 63:4888–4894PubMedGoogle Scholar
  18. 18.
    Joseph JD, Wittmann BM, Dwyer MA, Cui H, Dye DA, McDonnell DP, Norris JD (2009) Inhibition of prostate cancer cell growth by second-site androgen receptor antagonists. Proc Natl Acad Sci USA 106:12178–12183PubMedCrossRefGoogle Scholar
  19. 19.
    Jones JO, Bolton EC, Huang Y, Feau C, Guy RK, Yamamoto KR, Hann B, Diamond MI (2009) Non-competitive androgen receptor inhibition in vitro and in vivo. Proc Natl Acad Sci USA 106:7233–7238PubMedCrossRefGoogle Scholar
  20. 20.
    Sadar MD (1999) Androgen-independent induction of prostate-specific antigen gene expression via cross-talk between the androgen receptor and protein kinase a signal transduction pathways. J Biol Chem 274:7777–7783PubMedCrossRefGoogle Scholar
  21. 21.
    Ueda T, Bruchovsky N, Sadar MD (2002) Activation of the androgen receptor N-terminal domain by interleukin-6 via MAPK and STAT3 signal transduction pathways. J Biol Chem 277:7076–7085PubMedCrossRefGoogle Scholar
  22. 22.
    Guo Z, Yang X, Sun F, Jiang R, Linn DE, Chen H, Chen H, Kong X, Melamed J, Tepper CG, Kung HJ, Brodie AM, Edwards J, Qiu Y (2009) A novel androgen receptor splice variant is up-regulated during prostate cancer progression and promotes androgen depletion-resistant growth. Cancer Res 69:2305–2313PubMedCrossRefGoogle Scholar
  23. 23.
    Hu R, Dunn TA, Wei S, Isharwal S, Veltri RW, Humphreys E, Han M, Partin AW, Vessella RL, Isaacs WB, Bova GS, Luo J (2009) Ligand-independent androgen receptor variants derived from splicing of cryptic exons signify hormone-refractory prostate cancer. Cancer Res 69:16–22PubMedCrossRefGoogle Scholar
  24. 24.
    Sun S, Sprenger CC, Vessella RL, Haugk K, Soriano K, Mostaghel EA, Page ST, Coleman IM, Nguyen HM, Sun H, Nelson PS, Plymate SR (2010) Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant. J Clin Invest 120:2715–2730PubMedCrossRefGoogle Scholar
  25. 25.
    Hörnberg E, Ylitalo EB, Crnalic S, Antti H, Stattin P, Widmark A, Bergh A, Wikström P (2011) Expression of androgen receptor splice variants in prostate cancer bone metastases is associated with castration-resistance and short survival. PLoS One 6:e19059PubMedCrossRefGoogle Scholar
  26. 26.
    Quayle SN, Mawji NR, Wang J, Sadar MD (2007) Androgen receptor decoy molecules block the growth of prostate cancer. Proc Natl Acad Sci USA 104:1331–1336PubMedCrossRefGoogle Scholar
  27. 27.
    Metallo SJ (2010) Intrinsically disordered proteins are potential drug targets. Curr Opin Chem Biol 14:481–488PubMedCrossRefGoogle Scholar
  28. 28.
    Sadar MD, Williams DE, Mawji NR, Patrick BO, Wikanta T, Chasanah E, Irianto HE, Soest RV, Andersen RJ (2008) 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 10:4947–4950PubMedCrossRefGoogle Scholar
  29. 29.
    Andersen RJ, Mawji NR, Wang J, Wang G, Haile S, Myung JK, Watt K, Tam T, Yang YC, Bañuelos CA, Williams DE, McEwan IJ, Wang Y, Sadar MD (2010) Regression of castrate-recurrent prostate cancer by a small-molecule inhibitor of the amino-terminus domain of the androgen receptor. Cancer Cell 17:535–546PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  1. 1.Genome Sciences CentreBC Cancer AgencyVancouverCanada

Personalised recommendations