The University of Strathclyde has established a partnership with the Beatson Institute to initiate this multidisciplinary project, bringing together three academic researchers; Prof. Nick Tomkinson (Chemistry), Dr Blair Johnston (Modelling) and Prof. Karen Vousden (Biology). The project primarily applied a standard SAR approach following the design, target synthesis, biological evaluation and data analysis cycle, to develop a chemical probe for the emerging tumour suppression target, TP53 Induced Glycolysis and Apoptosis Regulator (TIGAR). Upon optimisation, these tool compounds were then used to dissect the fundamental biology associated with this target, specifically in cancer models developed within the Vousden laboratory.The phosphatase TIGAR plays a key role in the flow of metabolites within two key biological pathways; glycolysis and the pentose phosphate pathway (PPP). The regulation of these pathways is crucial for the stability and growth of cancer cells,which highlighted TIGAR as a potential therapeutic target. Currently, there are no chemical tools for the interrogation of TIGAR, and its downstream functional effects.Here, a novel series of 2-amino thiophene-3-cabomate benzoic acid derivatives were designed, synthesised, and biologically evaluated, as potential TIGAR inhibitors. A summary of the optimisation achieved during the SAR studies is highlighted in Figure 1, from initial hit compound 58 to lead compound 338. Ligand 338 exhibited a half-maximal inhibitory concentration in the nanomolar range. Pharmacokinetic studies demonstrated that 338 possessed a sufficiently robust PK profile for potential use within in vivo studies. The selectivity and cellular activity of lead compound 338 has yet to be tested, however, compound 184 exhibited a promising selectivity profile and phenocopied the effects of siRNA in cell based studies.
|Date of Award||1 Oct 2019|
- University Of Strathclyde
|Sponsors||University of Strathclyde|
|Supervisor||Nick Tomkinson (Supervisor) & Blair Johnston (Supervisor)|