PT  - JOURNAL ARTICLE
AU  - Gilles Ferry
AU  - Natacha Moulharat
AU  - Jean-Philippe Pradère
AU  - Patrice Desos
AU  - Anne Try
AU  - Annie Genton
AU  - Adeline Giganti
AU  - Monique Beucher-Gaudin
AU  - Michel Lonchampt
AU  - Marc Bertrand
AU  - Jean-Sébastien Saulnier-Blache
AU  - Gordon C. Tucker
AU  - Alex Cordi
AU  - Jean A. Boutin
TI  - S32826, A Nanomolar Inhibitor of Autotaxin: Discovery, Synthesis and Applications as a Pharmacological Tool
AID  - 10.1124/jpet.108.141911
DP  - 2008 Dec 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 809--819
VI  - 327
IP  - 3
4099  - http://jpet.aspetjournals.org/content/327/3/809.short
4100  - http://jpet.aspetjournals.org/content/327/3/809.full
SO  - J Pharmacol Exp Ther2008 Dec 01; 327
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