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Autotaxin (NPP-2/plasma lyso-PLD), discovered as a tumor cell motility factor, is overexpressed in various human cancers and stimulates angiogenesis, tumorigenesis, and metastasis in a mouse model. This exoenzyme catalyzes the production of lysophosphatidic acid (LPA), an extremely potent mediator of physiological and pathological processes including cancer. ATX is therefore an obvious extracellular therapeutic target. Thus far no small molecule inhibitors of ATX have been identified. Several histidine (His) residues within a metal binding site in ATX are required for activity. We tested the effects of free His and found that mM concentrations inhibit both the motogenic and enzymatic activities but have no effect on LPA-stimulated migration. Kinetic analysis indicated that the inhibition was non-competitive and was rescued by the addition of ZnSO4 at concentrations 20-fold lower than His. Comparison of His analogs indicated that the imidazole, as well as the carboxy and amino groups, are required for full inhibition. The uniquely potent properties of this natural amino acid may stimulate design of more effective agents against malignancy.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]