Supervisors: Professor Iain J. McEwan, Professor Andrew Porter, Dr Obinna Ubah (at partner)
Project Description:
Androgens are master regulators of cell function with well-established roles in regulation of anabolic metabolism and reproduction. The hormone testosterone acts through the androgen receptor, the ‘gate-keeper’ for androgen action. Testosterone replacement is used to treat hormone insufficiency and has the potential to improve conditions such as sarcopenia and frailty associated with ageing. To address excess androgen action, competitive hormone-binding antagonists are used to block receptor signalling. Our work has identified a structurally flexible region of the androgen receptor as a novel drug target. We have translated our knowledge in order to identify novel small molecule inhibitors with the potential to modulate receptor activity, independent of hormone-binding. We aim to exploit these findings together with the use of recombinant antibody technology to investigate the structure-function relationships of this domain of the receptor and its role in androgen signalling. The project will involve chemical modification of novel small molecule inhibitors to reveal their mode of action and improve their efficacy. We will generate a panel of single-chain antibodies, which can be delivered inside target cells to bind and ‘lock’ the conformation of the intrinsically-disordered amino-terminal domain of the receptor. Intrinsically disordered regions or domain are commonly found in regulatory proteins in the human proteome. Thus, the outcome of our studies will represent proof-of-principal for targeting these regions with biologics and the development of new drugs and tools to dissect the tissue-specific actions of androgens.
The student will receive training in molecular and cancer biology, immunology and medicinal chemistry methods specific to the project and in experimental design, data collection and analysis. The project will provide the student with a range of skills covering basic and more advanced cell and molecular techniques: including: antibody engineering; microscopy; and mammalian cell culture (reporter gene assays, siRNA knock down, western blotting, genome editing). Training in a range of data collection and analysis tools will be provided, together with the fundamentals on statistical treatment of the primary data. Collectively the programme of work will provide a stimulating and challenging experience for the student.
The Supervisors' laboratory is well equiped for molecular and cellular studies and is housed in the Institute of Medical Sciences, which provides access to a number of core facilities, including flow cytometry, microscopy, proteomics and a qPCR facility. The student will receive training in medininal chemistry through our collaboration with Dr Craig Jaimison (Strathclyde University). This will include analogue synthesis, structure-activity-relationships and ADME and PK studies.
The PhD student will spend a significant proportion of their PhD period based at Elasmogen’s premises in Aberdeen (max 18 months), and supervised by a world-class team of scientists with Dr Obinna Ubah (OU) taking the lead role as Company Supervisor. Working under the daily supervision of OU, the PhD will undertake research and knowledge embedding activities. Supervision will include monthly on-site meetings between Prof McEwan, and the student, and minuted quarterly management meetings (including OU) at the company. Meetings will review progress, set targets and identify obstacles. Access to UoA and Elasmogen facilities will be provided as required by the needs of the project.
References:
1. Hunter et al (2018) Tissue control of androgen action: The ups and downs of androgen receptor expression. Mol Cell Endocrinol. 465:27-35.
2. De Mol et al (2016) EPI-001, A Compound Active against Castration-Resistant Prostate Cancer, Targets Transactivation Unit 5 of the Androgen Receptor. ACS Chem Biol. 11(9):2499-505.
3. Myung et al (2013) An androgen receptor N-terminal domain antagonist for treating prostate cancer. J Clin Invest. 123(7):2948-60.
If you want to apply for this project, please go to this link.
