Synthetic Phospholipase D Inhibitors Block Cancer Metastasis

Drug developers have created a class of compounds that selectively inhibit isoforms of phospholipase D (PLD), an essential membrane-bound enzyme responsible for the production of the lipid second messenger phosphatidic acid (PA). PA participates in both G protein-coupled receptor and receptor tyrosine kinase signal transduction networks.

The current study was undertaken to correct the situation described by Dr. H. Alex Brown, professor of pharmacology at Vanderbilt University (Nashville, TN, USA): "PLD is associated with many fundamental cellular processes like secretion, migration, growth, and proliferation. But the absence of selective inhibitors has really interfered with the ability of biologists to study this important enzyme."

Dr. Brown continued, "Evidence from siRNA and other methods that blocking PLD resulted in dramatic effects of blocking metastatic invasion of breast cancer cells highly motivated us to attempt to make isoform-selective inhibitors."

As they reported in the January 11, 2009, online edition of the journal Nature Chemical Biology, Dr. Brown and his colleagues used a diversity-oriented synthetic approach to develop a library of PLD inhibitors with considerable pharmacological characterization. They found that specific compounds in the library inhibited isoforms of PLD with greater than 100-fold selectivity both in vitro and in cells. Furthermore, a subset of inhibitors was shown to block invasiveness in metastatic breast cancer models.

"These inhibitors are the key tools we need to really probe the biology, and we are obviously hoping to develop them for therapeutic applications too," said Dr. Brown.
Overall, these findings demonstrated the utility 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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