Isoform-specific phosphoinositide 3-kinase inhibitors from an arylmorpholine scaffold

Bioorg Med Chem. 2004 Sep 1;12(17):4749-59. doi: 10.1016/j.bmc.2004.06.022.


Phosphoinositide 3-kinases (PI3-Ks) are an ubiquitous class of signaling enzymes that regulate diverse cellular processes including growth, differentiation, and motility. Physiological roles of PI3-Ks have traditionally been assigned using two pharmacological inhibitors, LY294002 and wortmannin. Although these compounds are broadly specific for the PI3-K family, they show little selectivity among family members, and the development of isoform-specific inhibitors of these enzymes has been long anticipated. Herein, we prepare compounds from two classes of arylmorpholine PI3-K inhibitors and characterize their specificity against a comprehensive panel of targets within the PI3-K family. We identify multiplex inhibitors that potently inhibit distinct subsets of PI3-K isoforms, including the first selective inhibitor of p110beta/p110delta (IC(50) p110beta=0.13 microM, p110delta=0.63 microM). We also identify trends that suggest certain PI3-K isoforms may be more sensitive to potent inhibition by arylmorpholines, thereby guiding future drug design based on this pharmacophore.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Androstadienes / pharmacology*
  • Binding Sites
  • Cells, Cultured
  • Chromones / pharmacology*
  • Enzyme Inhibitors / pharmacology*
  • Inhibitory Concentration 50
  • Lipid Metabolism
  • Morpholines / pharmacology*
  • Phosphoinositide-3 Kinase Inhibitors*
  • Protein Isoforms / antagonists & inhibitors*
  • Protein Kinases / metabolism
  • Structure-Activity Relationship
  • Substrate Specificity
  • Wortmannin


  • Androstadienes
  • Chromones
  • Enzyme Inhibitors
  • Morpholines
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Isoforms
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Adenosine Triphosphate
  • Protein Kinases
  • Wortmannin