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CELLULAR AND MOLECULAR

S32826, A Nanomolar Inhibitor of Autotaxin: Discovery, Synthesis and Applications as a Pharmacological Tool

Pharmacologie Moléculaire et Cellulaire (G.F., N.M., A.T., A.Gi., J.A.B.) and Cancer Research and Drug Discovery Division (A.Ge., G.C.T.), Institut de Recherches SERVIER, Croissy-sur-Seine, France; Department of Metabolism and Obesity, Team 3, INSERM U858/I2MR, Toulouse, France (J.-P.P., J.-S.S.-B.); Division de Chimie Thérapeutique (P.D., A.C.) and Division des Maladies Métaboliques (M.B.-G., M.L.), Institut de Recherches SERVIER, Suresnes, France; and Technologie SERVIER, Orléans, France (M.B.)

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.

Address correspondence to: Jean A. Boutin, Pharmacologie Moléculaire et Cellulaire, Institut de Recherches SERVIER, 125, chemin de Ronde, 78290 Croissy-sur-Seine, France. E-mail: jean.boutin{at}fr.netgrs.com