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

197 Citations (Scopus)

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

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Phospholipase D
Protein Isoforms
Phosphatidic Acids
Neoplasms
Lipids
Receptor Protein-Tyrosine Kinases
Second Messenger Systems
G-Protein-Coupled Receptors
Libraries
Signal Transduction
Pharmacology
Breast Neoplasms
Enzymes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Scott, S. A., Selvy, P. E., Buck, J. R., Cho, H. P., Criswell, T. L., Thomas, A. L., ... 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

Design of isoform-selective phospholipase D inhibitors that modulate cancer cell invasiveness. / Scott, Sarah A.; Selvy, Paige E.; Buck, Jason R.; Cho, Hyekyung P.; Criswell, Tracy L.; Thomas, Ashley L.; Armstrong, Michelle D.; Arteaga, Carlos L.; Lindsley, Craig W.; Brown, H. Alex.

In: Nature Chemical Biology, Vol. 5, No. 2, 06.02.2009, p. 108-117.

Research output: Contribution to journalArticle

Scott, SA, Selvy, PE, Buck, JR, Cho, HP, Criswell, TL, Thomas, AL, Armstrong, MD, Arteaga, CL, Lindsley, CW & Brown, HA 2009, 'Design of isoform-selective phospholipase D inhibitors that modulate cancer cell invasiveness', Nature Chemical Biology, vol. 5, no. 2, pp. 108-117. https://doi.org/10.1038/nchembio.140
Scott, Sarah A. ; Selvy, Paige E. ; Buck, Jason R. ; Cho, Hyekyung P. ; Criswell, Tracy L. ; Thomas, Ashley L. ; Armstrong, Michelle D. ; Arteaga, Carlos L. ; Lindsley, Craig W. ; Brown, H. Alex. / Design of isoform-selective phospholipase D inhibitors that modulate cancer cell invasiveness. In: Nature Chemical Biology. 2009 ; Vol. 5, No. 2. pp. 108-117.
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