Structure-Activity Relationships of Small Molecule Autotaxin Inhibitors with a Discrete Binding Mode.
Lisa M MillerWillem-Jan KeuneDiana CastagnaLouise C YoungEmma L DuffyFrances PotjewydFernando Salgado-PoloPaloma Engel GarcíaDima SemaanJohn M PritchardAnastassis PerrakisSimon J F MacdonaldCraig JamiesonAllan J B WatsonPublished in: Journal of medicinal chemistry (2017)
Autotaxin (ATX) is a secreted enzyme responsible for the hydrolysis of lysophosphatidylcholine (LPC) to the bioactive lysophosphatidic acid (LPA) and choline. The ATX-LPA signaling pathway is implicated in cell survival, migration, and proliferation; thus, the inhibition of ATX is a recognized therapeutic target for a number of diseases including fibrotic diseases, cancer, and inflammation, among others. Many of the developed synthetic inhibitors for ATX have resembled the lipid chemotype of the native ligand; however, a small number of inhibitors have been described that deviate from this common scaffold. Herein, we report the structure-activity relationships (SAR) of a previously reported small molecule ATX inhibitor. We show through enzyme kinetics studies that analogues of this chemotype are noncompetitive inhibitors, and by using a crystal structure with ATX we confirm the discrete binding mode.