Proteolysis targeting chimeras (Protacs) are heterobifunctional small molecules which induce targeted protein degradation by hijacking the natural intracellular quality control mechanism, the ubiquitin-proteasome system. Protacs simultaneously bind both a target protein and an E3 ubiquitin ligase, forming a ternary complex. The close proximity of the target protein and the E3 ligase allows transfer of the post-translational modifier ubiquitin onto the target protein, which allows the protein to be recognised and degraded into small peptidic fragments by the proteasome. The Protac approach offers several advantages over small-molecule inhibition alone as efficacy can be driven from low drug concentrations, extended duration of action can be achieved, and scaffolding functions of the target protein can be removed. In this thesis, the application of Protac technology towards a series of disease-relevant proteins is explored. In Chapters 2 and 3, Protacs targeting the kinase ActR2B and the thyroid hormone receptor were developed as potential treatments for sarcopenia and hyperthyroidism, respectively. However, in both cases, no target degradation was observed. Given the lack of degradation with the initial empirically selected targets, a distinct, non-selective approach to protein degradation was considered in Chapter 4. Protacs based on a highly promiscuous kinase inhibitor were designed and synthesised, then profiled using proteome-wide expression proteomics. This strategy allowed identification of several novel degradable targets, and also indicated proteins that may be more challenging to degrade. The opportunity for degradation selectivity in the absence of binding selectivity was also highlighted. Having identified Bruton's tyrosine kinase (BTK) as one of these degradable targets, selective BTK Protacs were then studied in Chapter 5. Protacs based on the covalent inhibitor Ibrutinib led to the surprising discovery that covalent inhibition prevents Protac-mediated degradation of BTK. Protacs developed from a selective, reversible BTK inhibitor allowed rapid interrogation of the kinase as a prototypical Protac target.
|Date of Award||14 Sep 2017|
- University Of Strathclyde
|Sponsors||University of Strathclyde & Glaxo Smithkline (UK)|
|Supervisor||William Kerr (Supervisor) & Nick Tomkinson (Supervisor)|