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.