2. Academic Validation
  3. 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

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

  • J Med Chem. 2013 Mar 28;56(6):2695-9. doi: 10.1021/jm301782e.
Matthew C O'Reilly 1,  Sarah A Scott,  Kyle A Brown,  Thomas H Oguin 3rd,  Paul G Thomas,  J Scott Daniels,  Ryan Morrison,  H Alex Brown,  Craig W Lindsley
Affiliations

Affiliation

  • 1 Department of Pharmacology and ‡Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center , Nashville, Tennessee 37232, USA.
PMID: 23445448 DOI: 10.1021/jm301782e
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.

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