Cancer stem cell biology is controlled by the let-7 miRNA regulatory network (see Figure 1). Let-7 miRNAs suppress the expression of a number of key oncogenes including the RAS family, MYC, Bcl-2, HER2 and Lin28A. Let-7 miRNA maturation is controlled by terminal uridylyl transferase (TUT) enzymes in the cytoplasm which mono- or oligo-uridylate pre-let-7 miRNAs. Mono-uridylation leads to miRNA maturation and oncogene suppression. Oligo-uridylation is promoted by the cofactor Lin28A and leads to pre-let-7 degradation by the exonuclease DIS3L2. If we can inhibit the human TUTs then we may be able to develop a new therapeutic strategy that boosts endogenous miRNA levels. There is good evidence that a basis for patient stratification exists based on TUT over-expression and/or the presence of Lin28A. Data also indicate that reduction in TUT activity and the boosting of let-7 expression leads to chemo- and radio-sensitisation.
We solved the structure and defined the mechanism of a yeast homologue of the human TUTs which shows a high degree of conservation with the human enzymes (Yates et al., 2012, 2015) (Figure 2). We are now engaged in a drug discovery programme in which we have had success in identifying hits and showing efficacy of TUT inhibitors against the human enzymes. We are now expanding our programme to determine structures of the human enzymes in Apo and functional states and to develop further the drug discovery programme we have started using a combination of structural, biophysical, functional and cellular approaches. The project is also now part of an active commercial collaboration, providing further resources, and new opportunities for application of our findings. You would therefore join this project at a critical and exciting stage.
Our work builds on an excellent network of collaborators including industrial partners and (in Oxford) the Norbury lab based at the Dunn School that discovered terminal uridylylation, the Target Discovery Institute, and the Higgins lab in the Department of Oncology.