The Autotaxin-Lysophosphatidic acid (ATX-LPA) signalling pathway has been implicated in a variety of human disease states including angiogenesis, autoimmune diseases, cancer, fibrotic disease, inflammation, neurodegeneration, and neuropathic pain, amongst others. Two methods have been pursued in attempts to develop novel targets for this disease state which include: Route A – the development of novel LPA1 receptor antagonist, and Route B – the inhibition of the enzyme ATX required for the production of LPA (Scheme 1). Both of these routes will be pursued within this study with a view to developing novel targets for the inhibition of the LPA-ATX signalling pathway. Scheme 1: Proposed routes for the development of novel LPA-ATX inhibitors. A small compound library was constructed to target Route A, where of the compounds analysed none exhibited LPA1 receptor antagonism. Pleasingly, cross screening against ATX inhibition revealed several hit compounds, indicating the ability of cross-talk between these two signalling pathways. In regards to the second route, an extensive compound library was built based on the development of SAR surrounding a known potent ATX inhibitor by Amira Pharmaceuticals. The designed compounds were screened using a dual assay procedure (LPC and (bis-p-nitrophenyl)phosphate assay) which indicated a range of active compounds, as well as indicating the complexity associated with the binding mode of this particular motif.
|Date of Award||20 Apr 2016|
- University Of Strathclyde
|Sponsors||Glaxo Smithkline (UK)|
|Supervisor||Allan Watson (Supervisor) & Craig Jamieson (Supervisor)|