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Chemical Biology and Structure-based approaches to study novel induced-proximity modalities

Project Overview

Protein regulation by post-translational modifications (PTMs) is essential for cellular homeostasis. For example, protein phosphorylation, the most prevalent PTM, dynamically directs the function of proteins, with >130,000 phosphosites identified in human cells.1 Modulating proteins by inducing functional PTMs is thus highly desirable for therapeutic purposes but remains challenging with conventional drug discovery approaches.

Recently, novel pharmacological modalities that work by inducing protein proximity with small molecules have emerged.2,3 This mechanism of action was first conceptualised in the design of PROTACs (PROteolysis TArgeting Chimeras), which cause ubiquitination of target proteins by recruiting them to an E3 ligase using bispecific ligands. PROTACs induce polyubiquitination, a tag endogenously used to redirect proteins to degradation via the proteasome system, hence PROTACs have proven effective in inducing protein degradation on demand.

This project will look at integrating highly interdisciplinary structure-based and chemical biology approaches to study and develop novel ligands for induced proximity modalities, such as PHOSphorylation Targeting Chimers (PHOSTACs).4 In particular, you will explore covalent approaches to tackle challenging protein targets.5 Using cellular and in vitro model systems you will study the use of covalency within induced proximity modalities focusing on pharmacodynamic effects. This work will provide a thorough understanding of the advantages and disadvantages of combining these drug discovery modalities to modulate protein PTMs.

Research Environment

We are a group of Chemical Biologists at the Centre for Molecular and Cell Biology within the School of Biological and Behavioural Sciences (SBBS). As part of our team, you will master interdisciplinary skills in Drug Discovery and Chemical Biology ranging from organic synthesis to biochemical assays, protein crystallography and CryoEM, and molecular and cell biology including chemical proteomics. For this collaborative project, you will have access to cutting edge facilities across SBBS, including the Blizard Institute, a state-of-the-art centre for research. Visit our websites to find out more: https://edv-lab.com/; https://stieglitz-lab.com/.

Find out more about the School of Biological and Behavioural Sciences on our website.

Keywords: CHEMICAL BIOLOGY, DRUG DISCOVERY, COVALENT LIGANDS, INDUCED-PROXIMITY MODALITIES

Entry Requirements

We are looking for candidates to have or expecting to receive a first or upper-second class honours degree and a Master’s degree in an area relevant to the project such as Chemical Biology, Drug Discovery, Biochemistry or Structural Biology.

Knowledge of protein purification and biochemistry, organic synthesis, and molecular and cell biology techniques would be highly advantageous but are not required.

You must meet the IELTS requirements for your course and upload evidence before CSC’s application deadline, ideally by 1st March 2025. You are therefore strongly advised to sit an approved English Language test as soon as possible, where your IELTS test must still be valid when you enrol for the programme.

Please find further details on our English Language requirements page.

How to Apply

Formal applications must be submitted through our online form by 29th January 2025 for consideration. Please identify yourself as a ‘CSC Scholar’ in the funding section of the application.

Applicants are required to submit the following documents:

  • Your CV
  • Personal Statement
  • Evidence of English Language e.g.) IELTS Certificate
  • Copies of academic transcripts and degree certificates
  • References

Find out more about our application process on our SBBS website.

Informal enquiries about the project can be sent to Dr Elena De Vita AT e.devita@qmul.ac.uk Admissions-related queries can be sent to sbbs-pgadmissions@qmul.ac.uk

Shortlisted applicants will be invited for a formal interview by the supervisor. If you are successful in your QMUL application, then you will be issued an QMUL Offer Letter, conditional on securing a CSC scholarship along with academic conditions still required to meet our entry requirements.

Once applicants have obtained their QMUL Offer Letter, they should then apply to CSC for the scholarship with the support of the supervisor.

For further information, please go to the QMUL China Scholarship Council webpage.

Apply Online

References

  1. Liang, Z. et al. Deciphering the functional landscape of phosphosites with deep neural network. Cell Rep 42, 113048 (2023).
  2. Maneiro, M., De Vita, E., et al. PROTACs, molecular glues and bifunctionals from bench to bedside: Unlocking the clinical potential of catalytic drugs. (2021). In Progress in Medicinal Chemistry (1st ed.). Elsevier B.V. https://doi.org/10.1016/bs.pmch.2021.01.002
  3. Mullard, A. Proximity-inducing drugs get closer. Nat Rev Drug Discov; 22, 254–257 (2023).
  4. Zhang, Q. et al. Protein Phosphatase 5-Recruiting Chimeras for Accelerating Apoptosis-Signal-Regulated Kinase 1 Dephosphorylation with Antiproliferative Activity. J Am Chem Soc 145, 1118–1128 (2022).
  5. De Vita, E. 10 years into the resurgence of covalent drugs. Future Med Chem 13, 193–210 (2021).
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