RT Journal Article SR Electronic T1 S32826, A Nanomolar Inhibitor of Autotaxin: Discovery, Synthesis and Applications as a Pharmacological Tool JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 809 OP 819 DO 10.1124/jpet.108.141911 VO 327 IS 3 A1 Gilles Ferry A1 Natacha Moulharat A1 Jean-Philippe Pradère A1 Patrice Desos A1 Anne Try A1 Annie Genton A1 Adeline Giganti A1 Monique Beucher-Gaudin A1 Michel Lonchampt A1 Marc Bertrand A1 Jean-Sébastien Saulnier-Blache A1 Gordon C. Tucker A1 Alex Cordi A1 Jean A. Boutin YR 2008 UL http://jpet.aspetjournals.org/content/327/3/809.abstract AB Autotaxin catalyzes the transformation of lyso-phosphatidylcholine in lyso-phosphatidic acid (LPA). LPA is a phospholipid possessing a large panel of activity, in particular as a motility factor or as a growth signal, through its G-protein coupled seven transmembrane receptors. Indirect evidence strongly suggests that autotaxin is the main, if not the only source of circulating LPA. Because of its central role in pathologic conditions, such as oncology and diabetes/obesity, the biochemical properties of autotaxin has attracted a lot of attention, but confirmation of its role in pathology remains elusive. One way to validate and/or confirm its central role, is to find potent and selective inhibitors. A systematic screening of several thousand compounds using a colorimetric assay and taking advantage of the phosphodiesterase activity of autotaxin that requires the enzymatic site than for LPA generation, led to the discovery of a potent nanomolar inhibitor, [4-(tetradecanoylamino)benzyl]phosphonic acid (S32826). This compound was inhibitory toward the various autotaxin isoforms, using an assay measuring the [14C]lyso-phosphatidylcholine conversion into [14C]LPA. We also evaluated the activity of S32826 in cellular models of diabesity and oncology. Nevertheless, the poor in vivo stability and/or bioavailability of the compound did not permit to use it in animals. S32826 is the first reported inhibitor of autotaxin with an IC50 in the nanomolar range that can be used to validate the role of autotaxin in various pathologies in cellular models. The American Society for Pharmacology and Experimental Therapeutics