Autotaxin inhibition: challenges and progress toward novel anti-cancer agents

Autotaxin (ATX, autocrine motility factor, NPP2) has recently emerged as an attractive target for the development of anti-cancer chemotherapeutics. ATX contributes to the production of the bioactive lipid, lysophosphatidic acid (LPA), from lysophosphatidyl choline (LPC) in biological fluids including plasma, serum, and tumor cell effusates. LPA-stimulated cell proliferation, survival, motility and invasion have been demonstrated by numerous research groups. LPA receptors and ATX are upregulated in numerous cancer cell types and show expression patterns that correlate with tumor cell invasiveness. Despite considerable promise as an anti-cancer target, two complex challenges have slowed inhibitor discovery. The first of these challenges has been a lack of experimental details of the enzyme structure and its interactions with substrates or inhibitors. A second challenge has been a lack of structural diversity among initially reported inhibitors. Research reported in the last two years provides a foundation to begin addressing these challenges. Although an experimental structure of ATX is not among these recent developments, a crystal structure of the bacterial enzyme Xac. NPP is now available. This protein shares 35% identity with the central catalytic domain of ATX and provides an important starting point to begin understanding the structure of ATX. The structural diversity of known inhibitors has recently expanded to include not only phospholipid analogs, but also small molecules containing thiourea, diphenyldiazerenyl, anthracenedione and indole central cores. These two developments are essential tools for the discovery and optimization of ATX-targeted agents for evaluation as anti-cancer chemotherapeutic agents.