University College London Featured PhD Programmes
University of Glasgow Featured PhD Programmes
University of Edinburgh Featured PhD Programmes

EASTBIO: Bifunctional small molecules beyond PROTACs: Proximity-inducing new downstream chemistries to rewire cell signaling


   School of Life Sciences

This project is no longer listed on FindAPhD.com and may not be available.

Click here to search FindAPhD.com for PhD studentship opportunities
  Prof A Ciulli, Prof Gopal Sapkota  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

Dundee United Kingdom Biochemistry Biophysics Cell Biology Developmental Biology Pharmacology Structural Biology Toxicology

About the Project

Proteolysis targeting chimeras (PROTACs) are a popular class of bifunctional molecules that simultaneously engage a target protein on one end and an E3 ubiquitin ligase on the other end, forming a ternary complex that facilitates the rapid ubiquitylation and subsequent degradation of the target protein. PROTACs are revolutionizing drug discovery and therapeutic development by destroying rather than merely inhibiting a target protein. PROTACs leverage a novel unique modality of chemical intervention that we call “induced-proximity” – whereby the small molecule recruits a target protein close to an enzyme, inducing non-cognate protein-protein interactions between the two and as a result driving downstream chemistry to occur on the target protein as neo-substrate.

With this Studentship we seek to harness the principles of the mode of action of PROTACs via the ternary complex to develop and characterize a novel class of heterobifunctional molecules that bring the target protein into proximity to enzymes of a different class from E3 ligases – namely enzymes that natively regulate phosphorylation of substrate proteins. These molecules have the potential to expand the ways in which undruggable proteins can be targeted for proximity-induced chemistry beyond PROTACs, thereby significantly advance research and therapy.

The project will explore and test the hypothesis that specific targeted (de)phosphorylation will be different and potentially advantageous over and above conventional inhibition of target protein kinases or phosphatases. That is because it is expected to leverage specific from proximity-induced ternary complexes, and because modulating specific target phosphorylation level will be expected to fine-tune signaling pathways in a more precise way and without pathway re-wiring that e.g. kinase inhibitors are typically susceptible to. Furthermore, it is anticipated that such an approach of inducing proximity at sub-stoichiometric level for catalytic gain of function chemistry, will spare other functions of the target protein in ways that for example is not possible with targeted protein degradation where the entire protein is removed from cell.

The Ciulli Lab is one of the pioneering laboratories in the fields of PROTACs. The lab has innovated and qualified several popular and high-profile chemical probes protein-protein interactions and protein degradation, including VHL inhibitor VH298 and VHL degrader CM11, and BET protein degraders MZ1 and trivalent PROTAC SIM1. These are widely used by the scientific community as benchmark tool compounds to study biology. The Ciulli lab contributed to the field the first ever crystal structure of a ternary complex between a PROTAC and its E3 ligase and target proteins, illuminating unprecedented structural and mechanistic insights and guiding principles of how such bifunctional molecules work.

The Sapkota lab has expertise in studying reversible phosphorylation of proteins and pathways underpinning the regulation of cell signalling processes which account for many human diseases, including cancer and neurodegenerative diseases. The Sapkota lab developed an affinity directed protein missile (AdPROM) system that allows for rapid and efficient destruction of endogenous target proteins in cell lines. More recently, they have adapted the AdPROM system to induce proximity to protein phosphatases as a means to achieve robust targeted dephosphorylation of divergent set of proteins.


Funding Notes

Funding Notes
Eligibility
UKRI-funded studentships are open to students worldwide. The proportion of international students appointed through the EASTBIO DTP is capped at 30%. All students must meet the eligibility criteria as outlined in the UKRI Terms and Conditions (View Website - see TGC 5.2). To find out whether you would be classed as an International student, please see full residency criteria in Annex B of the accompanying guidance (View Website).
How to Apply
Please visit the School of Life Sciences EASTBIO page for more details View Website
Search Suggestions
Search suggestions

Based on your current searches we recommend the following search filters.

PhD saved successfully
View saved PhDs