Article abstract
Nature Chemical Biology 5, 108 - 117 (2009)
Published online: 11 January 2009 | doi:10.1038/nchembio.140
Design of isoform-selective phospholipase D inhibitors that modulate cancer cell invasiveness
Sarah A Scott1,5, Paige E Selvy1,5, Jason R Buck1, Hyekyung P Cho1, Tracy L Criswell2, Ashley L Thomas1, Michelle D Armstrong1, Carlos L Arteaga2,3, Craig W Lindsley1,4 & H Alex Brown1,4
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.
- 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.
- Department of Cancer Biology, Vanderbilt Institute of Chemical Biology, Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University School of Medicine, 2220 Pierce Avenue South, Nashville, Tennessee 37232-6600, USA.
- Department of Medicine, Vanderbilt Institute of Chemical Biology, Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University School of Medicine, 2220 Pierce Avenue South, Nashville, Tennessee 37232-6600, USA.
- Department of Chemistry, Vanderbilt Institute of Chemical Biology, Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University School of Medicine, 2220 Pierce Avenue South, Nashville, Tennessee 37232-6600, USA.
- These authors contributed equally to this work.
Correspondence to: H Alex Brown1,4 e-mail: alex.brown@vanderbilt.edu
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