Abstract
The androgen receptor (AR) is an important regulator of genes responsible for the development and recurrence of prostate cancer. Current therapies for this disease rely on small-molecule inhibitors that block the transcriptional activity of the AR. Recently, major advances in the development of novel AR inhibitors resulted from X-ray crystallographic information on the receptor and utilization of in silico drug design synergized with rigorous experimental testing.
Herein, we describe a drug-discovery pipeline for in silico screening for small molecules that target an allosteric region on the AR termed the binding-function 3 (BF3) site. Following the identification of potential candidates, the compounds are tested in cell culture and biochemical assays for their ability to interact with and inhibit the AR. The described pipeline is readily accessible and could be applied in drug design efforts toward any surface-exposed region on the AR or other related steroid nuclear receptor.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Green SM, Mostaghel EA, Nelson PS (2012) Androgen action and metabolism in prostate cancer. Mol Cell Endocrinol 360:3–13
Lallous N, Dalal K, Cherkasov A, Rennie PS (2013) Targeting alternative sites on the androgen receptor to treat castration-resistant prostate cancer. Int J Mol Sci 14:12496–12519
Jenster G, van der Korput HA, van Vroonhoven C, van der Kwast TH, Trapman J, Brinkmann AO (1991) Domains of the human androgen receptor involved in steroid binding, transcriptional activation, and subcellular localization. Mol Endocrinol 5:1396–1404
Cutress ML, Whitaker HC, Mills IG, Stewart M, Neal DE (2008) Structural basis for the nuclear import of the human androgen receptor. J Cell Sci 121:957–968
Lamont KR, Tindall DJ (2010) Androgen regulation of gene expression. Adv Cancer Res 107:137–162
Saad F, Miller K (2013) Treatment options in castration-resistant prostate cancer: current therapies and emerging docetaxel-based regimens. Urol Oncol 32(2):70–79
Bohl CE, Gao W, Miller DD, Bell CE, Dalton JT (2005) Structural basis for antagonism and resistance of bicalutamide in prostate cancer. Proc Natl Acad Sci U S A 102:6201–6206
Salvati ME, Balog A, Wei DD, Pickering D, Attar RM, Geng J, Rizzo CA, Hunt JT, Gottardis MM, Weinmann R, Martinez R (2005) Identification of a novel class of androgen receptor antagonists based on the bicyclic-1H-isoindole-1,3(2H)-dione nucleus. Bioorg Med Chem Lett 15:389–393
Duke CB, Jones A, Bohl CE, Dalton JT, Miller DD (2011) Unexpected binding orientation of bulky-B-ring anti-androgens and implications for future drug targets. J Med Chem 54:3973–3976
He B, Gampe RT Jr, Kole AJ, Hnat AT, Stanley TB, An G, Stewart EL, Kalman RI, Minges JT, Wilson EM (2004) Structural basis for androgen receptor interdomain and coactivator interactions suggests a transition in nuclear receptor activation function dominance. Mol Cell 16:425–438
Estebanez-Perpina 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 U S A 104:16074–16079
Lack NA, Axerio-Cilies P, Tavassoli P, Han FQ, Chan KH, Feau C, LeBlanc E, Guns ET, Guy RK, Rennie PS, Cherkasov A (2011) Targeting the binding function 3 (BF3) site of the human androgen receptor through virtual screening. J Med Chem 54:8563–8573
Jehle K, Cato L, Neeb A, Muhle-Goll C, Jung N, Smith EW, Buzon V, Carbo LR, Estebanez-Perpina E, Schmitz K, Fruk L, Luy B, Chen Y, Cox MB, Brase S, Brown M, Cato AC (2014) Coregulator control of androgen receptor action by a novel nuclear receptor-binding motif. J Biol Chem 289(13):8839–51
Munuganti RS, Leblanc E, Axerio-Cilies P, Labriere C, Frewin K, Singh K, Hassona MD, Lack NA, Li H, Ban F, Tomlinson Guns E, Young R, Rennie PS, Cherkasov A (2013) 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 56:1136–1148
Li H, Ren X, Leblanc E, Frewin K, Rennie PS, Cherkasov A (2013) Identification of novel androgen receptor antagonists using structure- and ligand-based methods. J Chem Inf Model 53:123–130
Li H, Ban F, Dalal K, LeBlanc E, Frewin K, Ma D, Rennie PS, Cherkasov A (2014) Discovery of small-molecule inhibitors selectively targeting the DNA-binding domain of the human androgen receptor. J Med Chem 57:6458–6467
Dalal K, Roshan-Moniri M, Sharma A, Li H, Ban F, Hessein M, Hsing M, Singh K, LeBlanc E, Dehm S, Guns ET, Cherkasov A, Rennie PS (2014) Selectively targeting the DNA binding domain of the androgen receptor as a prospective therapy for prostate cancer. J Biol Chem. doi:10.1074/jbc.M114.553818
Acknowledgements
This work was funded by Prostate Cancer Canada with generous support from Canada Safeway—Grant SP2013-02. This research was also supported by the Department of Defense (Prostate Cancer Res. Program) under award number (W81XWH-12-1-0401). Views and opinions of, and endorsements by, the authors do not reflect those of the US Army or the Department of Defense. The authors acknowledge the financial support from Canadian Institutes of Health Research and Canadian Cancer Society Research Institute grant F12-03271. R. Munuganti would like to thank Prostate Cancer Foundation-British Columbia (PCFBC), Canada, for providing graduate fellowship. K. Dalal is supported by CIHR and MSFHR postdoctoral fellowships.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2016 Springer Science+Business Media New York
About this protocol
Cite this protocol
Dalal, K., Munuganti, R., Morin, H., Lallous, N., Rennie, P.S., Cherkasov, A. (2016). Drug-Discovery Pipeline for Novel Inhibitors of the Androgen Receptor. In: McEwan, PhD, I. (eds) The Nuclear Receptor Superfamily. Methods in Molecular Biology, vol 1443. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-3724-0_4
Download citation
DOI: https://doi.org/10.1007/978-1-4939-3724-0_4
Published:
Publisher Name: Humana Press, New York, NY
Print ISBN: 978-1-4939-3722-6
Online ISBN: 978-1-4939-3724-0
eBook Packages: Springer Protocols