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

Scott SA, Selvy PE, Buck JR, Cho HP, Criswell TL, Thomas AL, Armstrong MD, Arteaga CL, Lindsley CW, Brown HA
Nat Chem Biol. 2009 5 (2): 108-17

PMID: 19136975 · PMCID: PMC3798018 · DOI:10.1038/nchembio.140

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.

MeSH Terms (7)

Breast Neoplasms Drug Design Enzyme Inhibitors Humans Isoenzymes Neoplasm Invasiveness Phospholipase D

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