Synthesis and biological evaluation of phosphonate derivatives as autotaxin (ATX) inhibitors

Autotaxin (ATX) is an autocrine motility factor that promotes cancer cell invasion, cell migration, and angiogenesis. ATX, originally discovered as a nucleotide phosphodiesterase, is known now to be responsible for the lysophospholipid-preferring phospholipase D activity in plasma. As such, it catalyzes the production of lysophosphatidic acid (LPA) from lysophophatidylcholine (LPC). ATX is thus an attractive drug target; small molecular inhibitors might be efficacious in slowing the spread of cancers. With this study we have generated a series of P-keto and P-hydroxy phosphonate derivatives of LPA, some of which are potent ATX inhibitors. (c) 2007 Elsevier Ltd. All rights reserved.