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Chem Biol Drug Des. 2014 Sep;84(3):270-81. doi: 10.1111/cbdd.12319. Epub 2014 Jun 3.

1,3-disubstituted-4-aminopyrazolo [3, 4-d] pyrimidines, a new class of potent inhibitors for phospholipase D.

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Department of Chemistry, University of Massachusetts Boston, 100 Morrissey Blvd, Boston, MA, 02125, USA.


Phospholipase D enzymes cleave lipid substrates to produce phosphatidic acid, an important precursor for many essential cellular molecules. Phospholipase D is a target to modulate cancer-cell invasiveness. This study reports synthesis of a new class of phospholipase D inhibitors based on 1,3-disubstituted-4-amino-pyrazolopyrimidine core structure. These molecules were synthesized and used to perform initial screening for the inhibition of purified bacterial phospholipase D, which is highly homologous to the human PLD1 . Initially tested with the bacterial phospholipase D enzyme, then confirmed with the recombinant human PLD1 and PLD2 enzymes, the molecules presented here exhibited inhibition of phospholipase D activity (IC50 ) in the low-nanomolar to low-micromolar range with both monomeric substrate diC4 PC and phospholipid vesicles and micelles. The data strongly indicate that these inhibitory molecules directly block enzyme/vesicle substrate binding. Preliminary activity studies using recombinant human phospholipase Ds in in vivo cell assays measuring both transphosphatidylation and head-group cleavage indicate inhibition in the mid- to low-nanomolar range for these potent inhibitory novel molecules in a physiological environment.


chemical biology; drug design; protease and ligands (substrate/inhibitor)

[Indexed for MEDLINE]

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