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Molecular Glues as Novel Therapies for Cancer and Ageing


   Molecular and Cell Biology

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  Dr Richard Doveston, Dr S Macip  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

Leicester United Kingdom Biophysics Cancer Biology Cell Biology Molecular Biology Structural Biology Synthetic Chemistry

About the Project

Background: The need for new medicines is greater than ever because of an ageing population and the complex clinical challenges brought about by drug resistance and/or side effects. These problems are particularly acute in the oncology therapeutic area and have a significant negative impact on society and the economy. As a result, the focus of oncology drug discovery has shifted in recent years away from classical enzyme inhibitors (e.g. kinase inhibitors) to even more challenging targets. Protein-protein interactions (PPI), and in particular inhibitors of these interactions, are at the forefront of this revolution: venetoclax has recently become the first PPI inhibitor approved for the treatment of chronic lymphocytic leukaemia. However, PPI inhibition alone does not fully exploit the potential scope and power of PPIs as drug targets.

Using drugs that act as molecular glues, to stabilise the interaction between proteins, is a highly novel therapeutic strategy that can greatly expand the number, effectiveness and precision of available treatments. This project will build on an exciting discovery in our labs. We have found that using a combination of molecular glues to target specific interactions of a family of ‘hub’ proteins called 14-3-3 effectively kills both proliferating and senescent cancer cells.

Project Aim: The aim of the project will be to optimise and refine this therapeutic approach. This will be acheived by studying the biological effects of the molecular glues in cells, and using a chemical biology approach to develop more efficacious and selective molecular glues. Ultimately we aim to deliver new drugs that can be translated into clinical use.

Methodology and Training: The project will be interdisciplinary in nature, combining elements of chemical biology, cellular biology, and structural biology. It will provide excellent training for students who are motivated to go to pursue careers in the field of cancer and ageing research, or pharmaceutical development.

Using cellular biology techniques such as cell viability assays, western blot and immunoprecipitation, and qPCR we will gain a better understanding of how the glues work in cancer cells. This understanding is essential to guide molecular glue design. At the molecular level we will use synthetic chemistry to synthesise novel glues, and a range of biophysical techniques to assess their stabilising effect on the specific protein-protein interactions we are targeting. We will also use protein X-ray crystallography to gain structural information in atomic detail.

Entry Requirements:

  • Those who have a 1st or a 2.1 undergraduate degree in a relevant field are eligible.
  • Evidence of quantitative training is required. For example, AS or A level Maths, IB Standard or Higher Maths, or university level maths/statistics course.
  • Those who have a 2.2 and an additional Masters degree in a relevant field may be eligible.
  • Those who have a 2.2 and at least three years post-graduate experience in a relevant field may be eligible.
  • Those with degrees abroad (perhaps as well as postgraduate experience) may be eligible if their qualifications are deemed equivalent to any of the above.

For further information please contact [Email Address Removed]

Application advice:

To apply please refer the application instructions at

https://le.ac.uk/study/research-degrees/funded-opportunities/bbsrc-mibtp

You will need to apply for the PhD place at University of Leicester and also submit your online application notification to MIBTP.  Links for both are on the above web page.

Project / Funding Enquiries: For further information please contact [Email Address Removed]

Application enquiries to [Email Address Removed] 


Funding Notes

All MIBTP students will be provided with a 4 years studentship.
Studentships include:
Tuition fees at UK rate*
• a tax free stipend of at least £15,609* p.a (to rise in line with UKRI recommendation)
• a travel allowance in year 1
• a travel / conference budget
• a generous consumables budget
• use of a laptop for the duration of the programme.
* International students are welcome to apply but must be able to fund the difference between UK
and International fees for the duration of their studies.

References

1. Doveston, Macip et al., Cell Death Discov. 2020, 6, 126.
2. Doveston et al., ACS Chem. Biol. 2020, 15, 262–271.
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