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

• Published in: Nature chemical biology Vol. 5; no. 2; pp. 108 - 117
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.02.2009; Nature Publishing Group
• Subjects: Biochemical Engineering; Biochemistry; Bioorganic Chemistry; Breast Neoplasms - pathology; Cancer; Cell Biology; Cellular biology; Chemistry; Chemistry and Materials Science; Chemistry/Food Science; Drug Design; Enzyme Inhibitors - pharmacology; Enzymes; Humans; Inhibitor drugs; Inhibitors; Invasiveness; Isoenzymes - pharmacology; Neoplasm Invasiveness - prevention & control; Phospholipase D - antagonists & inhibitors; Signal transduction
• ISSN: 1552-4450; 1552-4469; 1552-4469
• 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.