Journal
NATURE CHEMICAL BIOLOGY
Volume 5, Issue 2, Pages 108-117Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nchembio.140
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Funding
- A.B. Hancock Jr. Memorial Laboratory for Cancer Research
- Vanderbilt Institute for Chemical Biology
- US National Research Service [T32 GM007628]
- US National Cancer Institute [CA09592]
- Breast Cancer Specialized Program of Research Excellence [P50-CA98131]
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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.
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