Discovery of potent inhibitors of the lysophospholipase autotaxin
Copyright policy )Discovery of potent inhibitors of the lysophospholipase autotaxin
The autotaxin-lysophosphatidic acid (ATX-LPA) axis has been implicated in several disease conditions including inflammation, fibrosis and cancer. This makes ATX an attractive drug target and its inhibition may lead to useful therapeutic agents. Through a high throughput screen (HTS) we identified a series of small molecule inhibitors of ATX which have subsequently been optimized for potency, selectivity and developability properties. This has delivered drug-like compounds such as 9v (CRT0273750) which modulate LPA levels in plasma and are suitable for in vivo studies. X-ray crystallography has revealed that these compounds have an unexpected binding mode in that they do not interact with the active site zinc ions but instead occupy the hydrophobic LPC pocket extending from the active site of ATX together with occupying the LPA 'exit' channel.
- Cancer Research UK Manchester Institute United Kingdom
- Antoni van Leeuwenhoek Hospital Netherlands
- Cancer Research Technology United Kingdom
- University of Salford United Kingdom
- Netherlands Heart Institute Netherlands
Manchester Cancer Research Centre, Phosphoric Diester Hydrolases, Pyridines, Lysophosphatidic acid (LPA), Antineoplastic Agents, Autotaxin (ATX), Crystallography, X-Ray, ResearchInstitutes_Networks_Beacons/mcrc; name=Manchester Cancer Research Centre, Molecular Docking Simulation, Mice, Lysophosphatidylcholine (LPC), Neoplasms, Animals, Humans, Molecular Targeted Therapy, Enzyme Inhibitors, Lysophospholipids, Lysophospholipase, Cancer
Manchester Cancer Research Centre, Phosphoric Diester Hydrolases, Pyridines, Lysophosphatidic acid (LPA), Antineoplastic Agents, Autotaxin (ATX), Crystallography, X-Ray, ResearchInstitutes_Networks_Beacons/mcrc; name=Manchester Cancer Research Centre, Molecular Docking Simulation, Mice, Lysophosphatidylcholine (LPC), Neoplasms, Animals, Humans, Molecular Targeted Therapy, Enzyme Inhibitors, Lysophospholipids, Lysophospholipase, Cancer
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