title: Design of isoform-selective phospholipase D inhibitors that modulate cancer cell invasiveness.
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.
authors.affiliation: Department of Pharmacology, Vanderbilt Institute of Chemical Biology, Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University School of Medicine, 2220 Pierce Avenue South, Nashville, Tennessee 37232-6600, USA.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Scott
authors.forename: Paige E
authors.initials: PE
authors.lastname: Selvy
authors.forename: Jason R
authors.initials: JR
authors.lastname: Buck
authors.forename: Hyekyung P
authors.initials: HP
authors.lastname: Cho
authors.forename: Tracy L
authors.initials: TL
authors.lastname: Criswell
authors.forename: Ashley L
authors.initials: AL
authors.lastname: Thomas
authors.forename: Michelle D
authors.initials: MD
authors.lastname: Armstrong
authors.forename: Carlos L
authors.initials: CL
authors.lastname: Arteaga
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
authors.forename: H Alex
authors.initials: HA
authors.lastname: Brown
mesh_terms: D001943:Breast Neoplasms / Q000473:pathology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000494:pharmacology*; D009361:Neoplasm Invasiveness / Q000517:prevention & control*; D010739:Phospholipase D / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D007527:Isoenzymes; D010739:Phospholipase D