Chemical Evolution of Autotaxin Inhibitors

(ATX or ENPP2) was isolated as an autocrine motility factor from melanoma cells. 1 The ∼120 kDa glycoprotein ATX belongs to a small family named ectonucleotide pyrophosphatase and phosphodiesterase (ENPP), which consists of seven family members. 2 ATX is the only ENPP family member with lysophospholipase D (lysoPLD) activity and is responsible for the hydrolysis of lysophosphatidylcholine (LPC) to produce the bioactive lipid lysophosphatidic acid (LPA) (Scheme 1). 3,4 LPA acts on specific G-protein-coupled receptors and thereby stimulates the migration, proliferation, and survival of many cell types. 5,6 ATX is produced in various tissues and is the major LPA-producing enzyme in the circulation. After biosynthesis by ATX, LPA is subject to degradation by membrane-bound lipid phosphate phosphatases (LPPs).