Boronic acid-based inhibitor of autotaxin reveals rapid turnover of LPA in the circulation.
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.
Albers
Harald M H G
HM
Division of Cell Biology, Netherlands Proteomics Centre, Centre of Biomedical Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
Dong
Anping
A
van Meeteren
Laurens A
LA
Egan
David A
DA
Sunkara
Manjula
M
van Tilburg
Erica W
EW
Schuurman
Karianne
K
van Tellingen
Olaf
O
Morris
Andrew J
AJ
Smyth
Susan S
SS
Moolenaar
Wouter H
WH
Ovaa
Huib
H
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
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