| 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. |
| Authors | Sarah A Scott, Paige E Selvy, Jason R Buck, Hyekyung P Cho, Tracy L Criswell, Ashley L Thomas, Michelle D Armstrong, Carlos L Arteaga, Craig W Lindsley, H Alex Brown
(Affiliation: 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.)
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| Journal | Nature chemical biology
(Nat Chem Biol)
Vol. 5
Issue 2
Pg. 108-17
(Feb 2009)
ISSN: 1552-4469 United States |
| PMID | 19136975
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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