Design of isoform-selective phospholipase D inhibitors that modulate cancer cell invasiveness.
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.
Scott
Sarah A
SA
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.
Selvy
Paige E
PE
Buck
Jason R
JR
Cho
Hyekyung P
HP
Criswell
Tracy L
TL
Thomas
Ashley L
AL
Armstrong
Michelle D
MD
Arteaga
Carlos L
CL
Lindsley
Craig W
CW
Brown
H Alex
HA
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*
D004791:Enzyme Inhibitors; D007527:Isoenzymes; D010739:Phospholipase D