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Mol Pharmacol. 2015 Dec;88(6):982-92. doi: 10.1124/mol.115.100404. Epub 2015 Sep 14.

Structural Basis for Inhibition of Human Autotaxin by Four Potent Compounds with Distinct Modes of Binding.

Author information

1
Cayman Chemical Company, Ann Arbor, Michigan (A.J.S., N.M.P.S., R.S.S., J.S.); and PharmAkea, San Diego, California (G.B., P.P., A.M.S., J.D., L.G., D.L., I.C., J.F.E., J.H.H.).
2
Cayman Chemical Company, Ann Arbor, Michigan (A.J.S., N.M.P.S., R.S.S., J.S.); and PharmAkea, San Diego, California (G.B., P.P., A.M.S., J.D., L.G., D.L., I.C., J.F.E., J.H.H.) gbain@pharmakea.com.

Abstract

Autotaxin (ATX) is a secreted enzyme that hydrolyzes lysophosphatidylcholine to lysophosphatidic acid (LPA). LPA is a bioactive phospholipid that regulates diverse biological processes, including cell proliferation, migration, and survival/apoptosis, through the activation of a family of G protein-coupled receptors. The ATX-LPA pathway has been implicated in many pathologic conditions, including cancer, fibrosis, inflammation, cholestatic pruritus, and pain. Therefore, ATX inhibitors represent an attractive strategy for the development of therapeutics to treat a variety of diseases. Mouse and rat ATX have been crystallized previously with LPA or small-molecule inhibitors bound. Here, we present the crystal structures of human ATX in complex with four previously unpublished, structurally distinct ATX inhibitors. We demonstrate that the mechanism of inhibition of each compound reflects its unique interactions with human ATX. Our studies may provide a basis for the rational design of novel ATX inhibitors.

PMID:
26371182
DOI:
10.1124/mol.115.100404
[Indexed for MEDLINE]

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