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Synthesis and Characterisation of Proteolysis targeting chimeras (PROTACs), potential anticancer agents


About This PhD Project

Project Description

Proteolysis targeting chimeras (PROTACs) are bifunctional molecules consisting of a small molecule which binds a desired protein target, a linker, and a ligand which binds to an E3 ubiquitin ligase. Simultaneous binding of target and ligase brings the two proteins into close proximity, leading to ubiquitination and degradation of the protein target. The recent development of small molecule ligase ligands has led to an increase in popularity of the approach, and the potential to apply it in drug discovery.

The integrins are a family of transmembrane receptors which mediate cell-cell and cell-ECM adhesion, and signalling across the cell membrane involved in pathways controlling cell migration, proliferation, differentiation, cell survival and apoptosis. In cancers, their vital role in the cross-talk between the cell and extracellular matrix enhances the growth, migration, invasion and metastasis of cancer cells. The RGD-binding subfamily of integrins, comprising αvβ1,αvβ3,αvβ5,αvβ6,αvβ8, α5β1,α8β1,and αIIbβ3, are of particular interest, since there is strong evidence that their upregulation or ectopic expression on tumour tissues is correlated with tumour progression, treatment resistance, and a cancer stem cell phenotype. However, no integrin targeted small molecules or peptides have successfully reached the cancer clinic, due to problems with poor PKPD properties resulting in insufficient target coverage, and potential paradoxical effects at low drug concentrations.

PROTAC technology provides a strategy to overcome such problems in integrin targeting. PROTACS act catalytically and are effective at low doses –having bound the target protein molecule and triggered its degradation they can unbind and associate with another molecule of the target. This turns the reversible nature of competitive integrin antagonist binding into an advantage, and should avoid paradoxical effects. PROTACs do not require a long half-life or low clearance to be effective, their efficacy depends on a single binding event rather than the continued receptor occupation required by a competitive integrin antagonist, which simplifies the drug development process.

The aims of this project are to synthesise and to characterise the biological effects of a small library of integrin-targeted PROTACs to provide a preliminary demonstration of their potential as anticancer agents.

It is an exciting opportunity to work at the cutting edge of drug discovery, developing the first example of an integrin-targeting PROTAC agent.

References

Entry requirements:

At least 2.i Honours degree in chemistry - preferably medicinal chemistry - or related field such as biochemistry, or pharmacology with experience in synthetic chemistry

For full details of our entry requirements, please visit our website.

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