Project Description
This MRC/AstraZeneca funded iCASE PhD project will apply synthetic organic and medicinal chemistry, computational design, and biological testing to design and make compounds capable of triggering necroptotic cell death. This could form the basis of future combination treatment with immuno-oncology drugs, with potential therapeutic application across multiple cancer types.
Necroptosis is a highly immunogenic form of cell death, mediated by the pseudokinase MLKL. Phosphorylation of MLKL by RIPK3 is believed to be both necessary and sufficient to trigger dimerisation of the kinase-like domain. This in turn leads to further oligomerisation and membrane translocation of MLKL forming pores which disrupt membrane integrity leading to cell death.
Mediating gain-of-function events such as these therapeutically remains an unsolved problem. However, recent work has demonstrated that inducing proximity with heterobifunctional compounds represents a viable approach to switching on biological function. Induction of ubiquitination (via PROTAC) is now well validated, and early examples have progressed into the clinic. Activation of signalling by homodimerisation has been reported, and perhaps most relevant here, induction of phosphorylation of specific targets has now also been demonstrated both by Choudhary et al. and within our own team.
Therefore, the aim of this project is to design, synthesise, and test heterobifunctional compounds which can mediate phosphorylation and dimerisation of MLKL. These compounds will have the potential to trigger necroptotic cell death, providing a pathway to a novel therapeutic approach for cancer immunotherapy.
The student will gain valuable expertise in interdisciplinary research, building on their existing knowledge of organic synthetic chemistry. They will be supported by a supervisory team combining expertise in the medicinal chemistry of bifunctional compounds with a deep understanding of the mechanisms and consequences of necroptosis. Working within the Medicinal Chemistry team (Prof. Hoelder, Dr. Bellenie), the student will develop skills in medicinal chemistry, computational design and biological testing through hands-on experience, with one-to-one training from experienced postdoctoral scientists. They will benefit also from exposure to cancer cell biology through interactions with the Cell Death and Immunity team (Prof. Meier) and industrial research through a placement at AstraZeneca. Supporting this, our in-house training programmes, along with seminars from AZ speakers, will provide a broad understanding of drug discovery. Students will be supported to communicate their research widely, including writing up results for publication in peer-reviewed journals. As a result of their training, past students in our groups have readily found employment as scientists in academia or the pharmaceutical industry.
Keywords
- Pharmaceutical / Medicinal Chemistry
- Synthetic Chemistry
- Organic Chemistry
- Computational Chemistry
- Molecular and Cellular Pharmacology
- Cancer / Oncology
Candidate profile
Candidates must have a First class or Upper Second class BSc Honours/MSc in a relevant scientific subject, including some experience of synthetic organic chemistry.
How to apply
To view the full project proposal and details on how to apply using our online recruitment portal, please go to icr.ac.uk/phds. Please ensure that you read and follow the application instructions very carefully.
Please note we only accept applications via the online application system apply.icr.ac.uk.
Applications close at 11:55pm UK time on 14 November 2021
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