期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 107, 期 16, 页码 7257-7262出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1001529107
关键词
high-throughput screening; lysophosphatidic acid; lysophospholipase D; small-molecule inhibitor; phosphodiesterase
资金
- Netherlands Organization for Scientific Research (NWO)
- Dutch Cancer Society
- Center for Biomedical Genetics
- Netherlands Genomics Initiative
- National Institutes of Health (NIH) [HL074219, HL078663, GM050388]
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 (IC50 similar to 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.
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