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Nat Chem Biol. 2009 Feb;5(2):108-17. doi: 10.1038/nchembio.140. Epub 2009 Jan 11.

Design of isoform-selective phospholipase D inhibitors that modulate cancer cell invasiveness.

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1
Department of Pharmacology, Vanderbilt Institute of Chemical Biology, Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University School of Medicine, 2220 Pierce Avenue South, Nashville, Tennessee 37232-6600, USA.

Abstract

Phospholipase D (PLD) is an essential enzyme responsible for the production of the lipid second messenger phosphatidic acid. Phosphatidic acid participates in both G protein-coupled receptor and receptor tyrosine kinase signal transduction networks. The lack of potent and isoform-selective inhibitors has limited progress in defining the cellular roles of PLD. We used a diversity-oriented synthetic approach and developed a library of PLD inhibitors with considerable pharmacological characterization. Here we report the rigorous evaluation of that library, which contains highly potent inhibitors, including the first isoform-selective PLD inhibitors. Specific members of this series inhibit isoforms with >100-fold selectivity both in vitro and in cells. A subset of inhibitors was shown to block invasiveness in metastatic breast cancer models. These findings demonstrate the power of diversity-oriented synthesis combined with biochemical assays and mass spectrometric lipid profiling of cellular responses to develop the first isoform-selective PLD inhibitors--a new class of antimetastatic agents.

PMID:
19136975
PMCID:
PMC3798018
DOI:
10.1038/nchembio.140
[Indexed for MEDLINE]
Free PMC Article

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