Start Date: 1st October 2021
Background
The ability to degrade targeted proteins is an exciting and emerging new field of drug discovery, with the first drug candidates undergoing clinical evaluation. Their unique mechanism of action could enable powerful pharmacological effects of enormous potential benefit to patients by combining the advantages of small molecule and biological drugs, including:
- Completely eliminate their protein targets in a reversible and time-dependant manner.
- Work sub-stoichiometrically, meaning very low doses could be required to achieve an effect.
- Only target binding, not modulation of activity, is required to achieve their effect.
Whilst protein targeted chimeras (PROTACs) are the most well-developed and clinically advanced protein degradation technology their high molecular weight and chemical complexity makes delivery into the brain a significant challenge. This is despite the fact that a build up of mis-folded proteins is considered to be cause of several significant CNS disorders including Alzheimer’s (Tau protein), Creutzfeldt–Jakob disease (prion protein) and Huntington’s (Huntingtin protein). Other targeted approaches to protein degradation have been recently reported, potentially offering some advantages over the PROTAC approach in terms of application to CNS diseases. Promising novel approaches include autophagy mediated degradation (AUTAC and ATTEC) and ‘molecular glues’. The former approaches offer potential advantages in terms of the size of aggregate than be tolerated, whilst the latter achieves degradation using much lower molecular weight molecules with potential benefit for CNS penetration.
Project Aims
In collaboration with the global pharmaceutical company Janssen, the project will explore and evaluate the potential of these novel degradation approaches to ultimately treat various protein aggregate disorders including Alzheimer’s, Creutzfeldt–Jakob and Huntington’s diseases. The primary aim will be to determine which of the multiple emerging degradation approaches offers the greatest CNS penetration in general. This will be achieved through the synthesis of numerous examples of these new technologies and evaluation of these molecules in in vitro permeability (intestinal and brain) models and for their ability to degrade the targeted protein in vitro. Promising molecules may also be studied in vivo for their potential to degrade the target protein in the brain.
Applicant Skills
The ideal applicant will have a background in chemistry or medicinal chemistry with practical experience of the principles and practices of synthetic organic chemistry. Experience with basic cell biology techniques (cell culture) and basic biochemical assays would be an advantage, but the project will primarily be chemistry driven and support and training in biology skills will be provided.
Applicant Benefits
The applicant will benefit from working in the recently established (2018) Medicines Discovery Institute (MDI) at Cardiff University, which is staffed by experienced interdisciplinary drug discovery experts from academic and industrial backgrounds. In addition, the applicant will benefit from collaboration with the pharmaceutical industry (Janssen), including the possibility of a short-term placement at Janssen over the course of the project. The applicant will be afforded the opportunity to learn new skills beyond synthetic chemistry, whilst gaining first-hand experience of translationally oriented research. The protein degradation field is of intense academic and industrial interest and the project has significant potential for impact (conferences, publications etc.).
Please Note: Funding has been agreed in principle between the MDI and Janssen, pending formal completion of contracts. It is extremely likely this funding will be approved.
Eligibility
Candidates should hold an undergraduate degree in Chemistry or Medical Chemistry (minimum 2.1 grade, or 2.2 with a masters degree or additional relevant professional experience), and meet the University's English language entry requirements: https://www.cardiff.ac.uk/study/international/english-language-requirements/postgraduate
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