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

Nat Chem Biol. 2009 Feb;5(2):108-17. doi: 10.1038/nchembio.140. Epub 2009 Jan 11.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Breast Neoplasms / pathology
  • Drug Design
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Isoenzymes / pharmacology*
  • Neoplasm Invasiveness / prevention & control*
  • Phospholipase D / antagonists & inhibitors*

Substances

  • Enzyme Inhibitors
  • Isoenzymes
  • Phospholipase D

Associated data

  • PubChem-Substance/56427214
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