Luzac, Michal Leonie; (2008) Small Molecules as Potential Inhibitors of the Met Tyrosine Kinase Receptor. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The Met receptor tyrosine kinase, upon activation by its ligand HGF/SF, is crucially involved in both the physiological and pathological control of invasive growth. Furthermore, deregulation of Met activity is implicated in tumour proliferation, progression and metastasis, suggesting that this receptor is an attractive target for cancer therapy. Targeting receptor tyrosine kinases with small molecules directed at their ATP binding site has been shown to be a useful approach for drug discovery purposes. In addition, a crystallographic study of the kinase domain of Met complexed with the agent K252a has provided structural insights into the Met ATP binding site. The project involved the screening of a virtual library of 100,000 commercially available compounds against the ATP binding site of Met as a practical route to discovering new lead molecules. The compounds were docked and then ranked according to five scoring functions, utilising the molecular docking tool FlexX. In order to facilitate the selection of molecules for biological testing, a strategy was applied that involved molecular weight normalisation, consensus scoring, visual inspection of docked structures and clustering of structurally related molecules. Finally, 53 structures were selected from the virtual screen based on their predicted ability to dock into the ATP binding site of Met. Experimental validation of the selected compounds was achieved using a FRET-based kinase assay. One molecule, the tyrphostin AG213, emerged as a low-micromolar inhibitor of Met. In addition, studies were undertaken to investigate the effect of AG213 on Met activity in cellular systems. AG213 was shown to cause a decrease in HGF-dependent Met phosphorylation and cell scatter and a reduction of cell proliferation in cells with constitutively active Met, without affecting cell viability. These results suggest that AG213 could be used as a starting point for developing other more potent and potentially more selective Met inhibitors.

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