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Title: The amino terminal domain of steroid hormone receptors as a novel drug target : identification of small molecule inhibitors
Author: Monaghan, Amy Elizabeth
ISNI:       0000 0004 5993 0472
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2016
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Steroid hormone receptors (SHRs) are well validated therapeutic targets in a number of diseases. Current therapies competitively antagonise the ligand binding domain (LBD), blocking activation of the receptor and downstream signalling pathways. However cross-reactivity can be seen amongst the antagonists of different SHRs eliciting unwanted side effects. Additionally the acquisition of resistance to current therapies in diseases such as prostate cancer limits their use. The amino-terminal domain (NTD) of SHRs provides an alternative target for antagonism by allowing potential therapies to block receptor transactivation and inhibit interactions with co-activator proteins. Reduced homology between different SHR NTDs also increases the specificity of drug interactions. However development of targeted therapies using rational drug design has been hindered by its intrinsically disordered structure. Establishing cell lines which stably express a SHR responsive reporter gene alongside variants of SHRs lacking the LBD provides a method by which small molecules specifically targeting the NTD of each receptor can be identified. This assay has been designed to overcome the barriers to drug discovery that are presented by an intrinsically disordered protein. The project follows the design, development, optimisation and implementation of a high throughput screening assay with the potential to identify novel small molecule inhibitors of SHRs. The applications of these inhibitors are highlighted throughout, with specific reference to their potential to inhibit the androgen receptor in prostate cancer.
Supervisor: McEwan, I. J. Sponsor: Biotechnology and Biological Sciences Research Council (BBSRC) ; IOMet Pharma ; Friends of Anchor
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Steroid hormones ; Nuclear receptors (Biochemistry) ; Antiandrogens ; Prostate