Development of Dual PLD1/2 and PLD2 Selective Inhibitors From a Common 138-Triazaspiro4.5decane Core: Discovery of ML298 and ML299 that Decrease Invasive Migration in U87-MG Glioblastoma Cells

摘要

An iterative parallel synthesis effort identified a PLD2 selective inhibitor, ML298 (PLD1 IC50 >20,000 nM, PLD2 IC50 = 355 nM) and a dual PLD1/2 inhibitor, ML299 (PLD1 IC50 = 6 nM, PLD2 IC50 = 20 nM). SAR studies revealed 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.