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Investigating the druggability of the motif-mediated interactome with peptide PROTACs

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  • Full or part time
    Dr N Davey
    Dr S Guettler
    Prof J Pines
  • Application Deadline
    No more applications being accepted
  • Funded PhD Project (UK Students Only)
    Funded PhD Project (UK Students Only)

About This PhD Project

Project Description

The Institute of Cancer Research, London, is one of the world’s most influential cancer research institutes. We are committed to attracting and developing the best minds in the world to join us in our mission—to make the discoveries that defeat cancer.

Investigating the druggability of the motif-mediated interactome with peptide PROTACs

We are recruiting a highly motivated team member on a 4-year MRC industrial Collaborative Awards in Science and Engineering (iCASE) studentship. The project is a collaboration between Merck and the ICR Division of Cancer Biology. The project will characterise PROteolysis TArgeting Chimeras (PROTACs) against Short, Linear Motif (SLiM) binding pockets to identify targets for therapeutic intervention.

SLiMs are ubiquitous compact interaction interfaces that direct key cellular processes. PROTACs targeting SLiM-binding pockets can specifically promote ubiquitin ligase-dependent degradation of regulatory proteins in critical cellular pathways. We will apply a scalable method using genetically encoded peptide PROTACs to provide proof of principle for the therapeutic relevance of targeted degradation of essential proteins. Peptide PROTACs provide a fast and cost-effective approach to mirror the mode of action of a small molecule PROTAC, providing evidence for the spatiotemporal compatibility of the E3 and target, and the phenotype of target protein degradation.
The aim of the project is to determine the relevance of targeted degradation of the SLiM-binding proteins as a cancer therapy.
● To design and undertake experiments appropriate for the project, working in a semi-independent fashion involving the following:
○ Development of an optimised scaffold construct for an inducible genetically-encoded heterobifunctional peptide PROTAC
○ Construction of cell lines expressing peptide PROTACs
○ Assay the ability of peptide PROTACs to promote the degradation of the targeted proteins and to modulate cell viability
○ Interpretation of the findings and design of future experiments.
○ Maintain accurate records of experiments and data.
● To coordinate with other members of the team and the Division and contribute to a multidisciplinary collaboration through providing scientific input into a developing research project.
● To further develop a knowledge of the literature in the subject area.
● Presentation of seminars and journal clubs.
● Writing drafts of publications arising from this work.

One or more of the following skills are desirable (but not required):
• Proficiency in human cell line development
• Knowledge and experience of fluorescence microscopy or degradation assays
• Understanding of biological concepts relevant to the project

Keywords /Subject Areas:
Proteolysis targeting chimeras (PROTACs)
E3 Ubiquitin Ligases
Protein-Protein Interactions
Drug lead discovery
Synthetic biology

Funding Notes

Stipend, currently £21,000 per annum, tuition fees and project costs paid for the four-year duration. To be eligible for a full award a student must have no restrictions on how long they can stay in the UK and have been ordinarily resident in the UK for at least 3 years prior to the start of the studentship. Please see the MRC residency requirements for further information.

See to apply
Applications close 11:55pm UK time on Sunday 17th November 2019
Candidates must have a first class or upper second class honours BSc Honours/MSc in Biology, Biochemistry or Chemistry.

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