The Amino-terminal Domain of Steroid Receptors as a Novel Drug Target: Identification and Characterisation of Inhibitors Molecules:
Steroid hormones regulate a wide range of physiological processes from the control of reproduction to metabolism. These molecules act via intracellular receptor proteins, which function as ligand-activated transcription factors. Steroid receptors (SHRs) also represent a well validated drug target for the treatment of some of the major health concerns in the developed world including hormone-dependent cancers, inflammation and cardiovascular disease (CVD). Currently, therapeutic intervention involves blocking synthesis of the natural hormone coupled with the use of antagonists, which bind to the receptor protein but fail to activate the normal signalling cascade. However the effectiveness of such treatments can be compromised by side-effects or the emergence of resistance to steroid antagonists. Recent evidence suggests that the structurally flexible N-terminal domain of SHRs may represent an effective drug target to switch off receptor signalling by interfering with protein-protein interactions (PPi)
The NTD of SHRs is important for receptor activity and is involved in multiple PPi with the transcription machinery. Targeting this region of the receptor with inhibitor molecules is likely to be effective at shutting off receptor activity irrespective of the hormone binding status of the protein.
Project 1. The Androgen Receptor Amino-terminal Domain: A Novel Drug Target for the Treatment of Castrate Resistant Prostate Cancer.
Funding: The Prostate Cancer Charity, KCT
Project 2. The Amino-terminal Domain of Steroid Receptors as a Novel Drug Target: Identification and Characterisation of Small Molecule Inhibitors.
Funding: BBSRC-CASE studentship with TPP Global Development
Project Team: Professor Iain J. McEwan, Professor Matteo Zanda
1. Andersen, RJ, Mawji, NR, Wang, J, Wang, G, Haile, S, Myung, J-K, Watt, K, Tam, T, Yang, YC, Bañuelos, CA, Williams, DE, McEwan, IJ, Wang, Y and 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, 535-546.
2. McEwan, IJ. (2011) Intrinsic disorder in the androgen receptor: identification, characterisation and drugability. Mol Biosyst. 2[Epub ahead of print] DOI: 10.1039/c1mb05249g.