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dc.contributor.authorShah, P
dc.contributor.authorCheasty, A
dc.contributor.authorFoxton, C
dc.contributor.authorRaynham, T
dc.contributor.authorFarooq, M
dc.contributor.authorGutierrez, I
dc.contributor.authorLejeune, A
dc.contributor.authorPritchard, M
dc.contributor.authorTurnbull, A
dc.contributor.authorPang, L
dc.contributor.authorOwen, P
dc.contributor.authorBoyd, S
dc.contributor.authorStowell, Alexandra I J
dc.contributor.authorJordan, Allan M
dc.contributor.authorHamilton, Niall M
dc.contributor.authorHitchin, James R
dc.contributor.authorStockley, M
dc.contributor.authorMacDonald, E
dc.contributor.authorQuesada, M
dc.contributor.authorTrivier, E
dc.contributor.authorSkeete, J
dc.contributor.authorOvaa, H
dc.contributor.authorMoolenaar, W
dc.contributor.authorRyder, H
dc.date.accessioned2016-11-18T12:39:43Z
dc.date.available2016-11-18T12:39:43Z
dc.date.issued2016-10-14
dc.identifier.citationDiscovery of potent inhibitors of the lysophospholipase autotaxin. 2016 Bioorg. Med. Chem. Lett.en
dc.identifier.issn1464-3405
dc.identifier.pmid27780639
dc.identifier.doi10.1016/j.bmcl.2016.10.036
dc.identifier.urihttp://hdl.handle.net/10541/620020
dc.description.abstractThe autotoxin-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 of ATX together with the occupying the LPA 'exit' channel.
dc.languageENG
dc.rightsArchived with thanks to Bioorganic & medicinal chemistry lettersen
dc.titleDiscovery of potent inhibitors of the lysophospholipase autotaxin.
dc.typeArticleen
dc.contributor.departmentCancer Research Technology, Discovery Laboratories, Babraham Research Campus, Cambridge CB22 3AT, UKen
dc.identifier.journalBioorganic & Medicinal Chemistry Lettersen
html.description.abstractThe autotoxin-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 of ATX together with the occupying the LPA 'exit' channel.


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