Wood, Andrew

Boulter, Luke

Gudauskaitė, Evelina

2024-10-30T12:26:06Z

2024-10-30T12:26:06Z

2024-10-30

Protein degrader drugs such as PROTACs have emerged as a chemical strategy to degrade pathological proteins via recruitment to E3 ubiquitin ligase complexes. How the basal rate of target protein turnover influences PROTAC-mediated degradation is incompletely understood. To address this question, I focused on the oncogenic transcription factor β-catenin, which is activated in human cancer by a variety of stabilising mutations within a degron motif. Here, I use a synthetic degron tag system to compare the kinetics of different PROTAC degraders on β-catenin activated via oncogenic stabilising mutations of different strengths. Interestingly, even an approximately fivefold increase in stability levels resulted in similar absolute protein levels after PROTACs-mediated degradation. This finding suggests that the maximum degradation was not solely determined by protein stability. Additionally, it showed that PROTACs can override natural rates of protein turnover, even when they have been disrupted by oncogenic mutations. Understanding this could help to predict how well patients with different oncogenic mutations will respond to PROTAC therapy.

https://hdl.handle.net/1842/42384

http://dx.doi.org/10.7488/era/5078

en

The University of Edinburgh

β-catenin

mutations in β-catenin

PROTAC-mediated degradation kinetics

Protein degrader

E3 ubiquitin ligase complexes

oncogenic transcription factor

PROTAC

Effect of stabilising mutations in β-catenin on PROTAC-mediated degradation kinetics

The effect of stabilising mutations in β-catenin on PROTAC-mediated degradation kinetics

Thesis or Dissertation

Masters

MSc(R) Master of Science by Research