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

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

Research output: Contribution to journalArticle

207 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)108-117
Number of pages10
JournalNature chemical biology
Volume5
Issue number2
DOIs
StatePublished - Feb 6 2009

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Scott, S. A., Selvy, P. E., Buck, J. R., Cho, H. P., Criswell, T. L., Thomas, A. L., Armstrong, M. D., Arteaga, C. L., Lindsley, C. W., & Brown, H. A. (2009). Design of isoform-selective phospholipase D inhibitors that modulate cancer cell invasiveness. Nature chemical biology, 5(2), 108-117. https://doi.org/10.1038/nchembio.140