title: Development of dual PLD1/2 and PLD2 selective inhibitors from a common 1,3,8-Triazaspiro[4.5]decane Core: discovery of Ml298 and Ml299 that decrease invasive migration in U87-MG glioblastoma cells.
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.
authors: Department of Pharmacology and ‡Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center , Nashville, Tennessee 37232, USA.
authors: Matthew C
authors: MC
authors: O'Reilly
authors: Sarah A
authors: SA
authors: Scott
authors: Kyle A
authors: KA
authors: Brown
authors: Thomas H
authors: TH
authors: Oguin
authors: Paul G
authors: PG
authors: Thomas
authors: J Scott
authors: JS
authors: Daniels
authors: Ryan
authors: R
authors: Morrison
authors: H Alex
authors: HA
authors: Brown
authors: Craig W
authors: CW
authors: Lindsley
mesh_terms: D001549:Benzamides / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D005909:Glioblastoma / Q000473:pathology*; D006801:Humans; D009361:Neoplasm Invasiveness; D010739:Phospholipase D / Q000037:antagonists & inhibitors*; D013141:Spiro Compounds / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: C581212:3,4-difluoro-N-(2-(1-(3-fluorophenyl)-4-oxo-1,3,8-triazaspiro(4.5)decan-8-yl)ethyl)benzamide; D001549:Benzamides; D004791:Enzyme Inhibitors; C581213:ML299; D013141:Spiro Compounds; C105606:phospholipase D2; D010739:Phospholipase D; C106801:phospholipase D1