title: Boronic acid-based inhibitor of autotaxin reveals rapid turnover of LPA in the circulation.
abstract: Autotaxin (ATX) is a secreted nucleotide pyrophosphatase/phosphodiesterase that functions as a lysophospholipase D to produce the lipid mediator lysophosphatidic acid (LPA), a mitogen, chemoattractant, and survival factor for many cell types. The ATX-LPA signaling axis has been implicated in angiogenesis, chronic inflammation, fibrotic diseases and tumor progression, making this system an attractive target for therapy. However, potent and selective nonlipid inhibitors of ATX are currently not available. By screening a chemical library, we have identified thiazolidinediones that selectively inhibit ATX-mediated LPA production both in vitro and in vivo. Inhibitor potency was approximately 100-fold increased (IC(50) approximately 30 nM) after the incorporation of a boronic acid moiety, designed to target the active-site threonine (T210) in ATX. Intravenous injection of this inhibitor into mice resulted in a surprisingly rapid decrease in plasma LPA levels, indicating that turnover of LPA in the circulation is much more dynamic than previously appreciated. Thus, boronic acid-based small molecules hold promise as candidate drugs to target ATX.
authors.affiliation: Division of Cell Biology, Netherlands Proteomics Centre, Centre of Biomedical Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
authors.forename: Harald M H G
authors.initials: HM
authors.lastname: Albers
authors.forename: Anping
authors.initials: A
authors.lastname: Dong
authors.forename: Laurens A
authors.initials: LA
authors.lastname: van Meeteren
authors.forename: David A
authors.initials: DA
authors.lastname: Egan
authors.forename: Manjula
authors.initials: M
authors.lastname: Sunkara
authors.forename: Erica W
authors.initials: EW
authors.lastname: van Tilburg
authors.forename: Karianne
authors.initials: K
authors.lastname: Schuurman
authors.forename: Olaf
authors.initials: O
authors.lastname: van Tellingen
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Morris
authors.forename: Susan S
authors.initials: SS
authors.lastname: Smyth
authors.forename: Wouter H
authors.initials: WH
authors.lastname: Moolenaar
authors.forename: Huib
authors.initials: H
authors.lastname: Ovaa
mesh_terms: D000818:Animals; D001897:Boronic Acids / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006023:Glycoproteins / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D008055:Lipids / Q000737:chemistry; D008246:Lysophospholipids / Q000378:metabolism*; D008297:Male; D051379:Mice; D009097:Multienzyme Complexes / Q000378:metabolism; D043264:Phosphodiesterase I / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry; D011755:Pyrophosphatases / Q000378:metabolism; D015398:Signal Transduction; D045162:Thiazolidinediones / Q000737:chemistry; D000099189:Lysophospholipase D
chemical_list: D001897:Boronic Acids; D006023:Glycoproteins; D008055:Lipids; D008246:Lysophospholipids; D009097:Multienzyme Complexes; D043264:Phosphodiesterase I; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases; D045162:Thiazolidinediones; D000099189:Lysophospholipase D; C032881:lysophosphatidic acid