Abstract
An iterative parallel synthesis effort identified a PLD2 selective inhibitor, ML298 (PLD1 IC50 > 20000 nM, PLD2 IC50 = 355 nM) and a dual PLD1/2 inhibitor, ML299 (PLD1 IC50 = 6 nM, PLD2 IC50 = 20 nM). SAR studies revealed that a small structural change (incorporation of a methyl group) increased PLD1 activity within this classically PLD2-preferring core and that the effect was enantiospecific. Both probes decreased invasive migration in U87-MG glioblastoma cells.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Benzamides / chemistry*
-
Benzamides / metabolism
-
Benzamides / pharmacokinetics
-
Benzamides / pharmacology*
-
Cell Line, Tumor
-
Cell Movement / drug effects*
-
Drug Discovery*
-
Enzyme Inhibitors / chemistry
-
Enzyme Inhibitors / metabolism
-
Enzyme Inhibitors / pharmacokinetics
-
Enzyme Inhibitors / pharmacology
-
Glioblastoma / pathology*
-
Humans
-
Neoplasm Invasiveness
-
Phospholipase D / antagonists & inhibitors*
-
Spiro Compounds / chemistry*
-
Spiro Compounds / metabolism
-
Spiro Compounds / pharmacokinetics
-
Spiro Compounds / pharmacology*
Substances
-
3,4-difluoro-N-(2-(1-(3-fluorophenyl)-4-oxo-1,3,8-triazaspiro(4.5)decan-8-yl)ethyl)benzamide
-
Benzamides
-
Enzyme Inhibitors
-
ML299
-
Spiro Compounds
-
phospholipase D2
-
Phospholipase D
-
phospholipase D1