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Cytoplasmic terminal polymerases: small molecule opportunities to target the microRNA pathway (TUTCHEM)
Start date: Nov 1, 2012, End date: Oct 31, 2013 PROJECT  FINISHED 

"MicroRNAs (miRNAs) are a novel class of human disease genes that are key to a number of therapeutic areas in particular cancer, and also heart disease, infectious disease and ageing. Specifically, some miRNAs are known to regulate cancer therapeutic targets acting as tumour suppressors and some are prognostic and diagnostic markers of human disease. The requirement for targeted anti-cancer therapies to effect specific disease treatment is well established and considered a primary goal for moving cancer towards a treatable, controllable chronic condition.miRNA-based therapeutics is a well-occupied space. However, existing commercial efforts and IP is focused on the use of oligonucleotides and oligonucleotide derivatives to inhibit or modulate the expression of miRNAs. Such efforts have been largely limited by the challenges associated with poor delivery.Instead we have identified novel opportunities to target miRNA pathways using small molecules. Specifically, we discovered a novel class of enzymes (TUTases) that regulate miRNAs by terminal polyuridylation. We found that a specific member of this family (Tut4) acts to inhibit the tumour suppressor miRNA let-7 in a model organism and human cancer cells. TUTases likely provide multiple novel anti-cancer targets. For example, the Tutase Gld2 was recently shown to regulate the p53 tumour suppressor pathway by modifying the miR-122 miRNA.We have developed an efficient in vitro assay of Tut4 activity. Here, we want to develop this assay into a high-throughput screening platform to identify small molecule inhibitors of Tutases. Such small molecules are proof-of-concept molecules for a novel anti-cancer strategy."

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