With the invention of PROteolysis Targeting Chimeras (PROTACs) in 2001, targeted protein degradation (TPD) has revolutionised the landscape of drug discovery. PROTACs recruit endogenous cellular machinery (E3 ubiquitin ligase proteins) to degrade a target protein to modulate its function as opposed to direct inhibition. This novel therapeutic modality opens new possibilities to target proteins once deemed ‘undruggable’ and potentially overcome drug resistance. Protein degraders have been widely explored and have outperformed several approved medicines in in vivo models, notably for the treatment of various cancers. Despite this, progression in the field is hindered by the lack of small molecule ligands available for E3 ubiquitin ligase proteins. In general, E3 ubiquitin ligases are regarded as challenging targets in drug discovery due to the high affinity to endogenous substrates and shallow binding pockets, because of this less than 3% of the ~600-member family have reported ligands.
This project describes work undertaken to discover new chemical matter for a previously unliganded E3 ubiquitin ligase – TRIM22. This was achieved through reactive fragment screening and subsequent follow-up library design and screening. A chosen reactive fragment ligand of TRIM22 was then functionalised into an active degrader of the epigenetic protein BRD4, a classic target in oncology. This compound has been profiled extensively through orthogonal assays successfully confirming degradation of BRD4. The role of TRIM22 in the degradation of BRD4 was then investigated through genetic editing and chemoproteomics.
Overall, the work in this thesis exemplifies the utility of reactive fragment screening to identify high quality starting points for a previously unliganded E3 ubiquitin ligase, a family of proteins often considered challenging to ligand. It is anticipated the workflow devised in this research could be applied to other unliganded E3 ligases, simultaneously expanding the liganded proteome and the therapeutic reach of target protein degradation.
| Date of Award | 24 May 2024 |
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| Original language | English |
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| Awarding Institution | - University Of Strathclyde
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| Sponsors | University of Strathclyde |
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| Supervisor | Glenn Burley (Supervisor) & Craig Jamieson (Supervisor) |
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