A Pan-GTPase Inhibitor as a Molecular Probe

PLoS One. 2015 Aug 6;10(8):e0134317. doi: 10.1371/journal.pone.0134317. eCollection 2015.

Abstract

Overactive GTPases have often been linked to human diseases. The available inhibitors are limited and have not progressed far in clinical trials. We report here a first-in-class small molecule pan-GTPase inhibitor discovered from a high throughput screening campaign. The compound CID1067700 inhibits multiple GTPases in biochemical, cellular protein and protein interaction, as well as cellular functional assays. In the biochemical and protein interaction assays, representative GTPases from Rho, Ras, and Rab, the three most generic subfamilies of the GTPases, were probed, while in the functional assays, physiological processes regulated by each of the three subfamilies of the GTPases were examined. The chemical functionalities essential for the activity of the compound were identified through structural derivatization. The compound is validated as a useful molecular probe upon which GTPase-targeting inhibitors with drug potentials might be developed.

Publication types

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

MeSH terms

  • Apoptosis / drug effects
  • Cell Line
  • Cell Survival / drug effects
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology
  • ErbB Receptors / metabolism
  • GTP Phosphohydrolases / antagonists & inhibitors*
  • GTP Phosphohydrolases / genetics
  • GTP Phosphohydrolases / metabolism
  • HeLa Cells
  • Heterocyclic Compounds, 2-Ring / chemical synthesis
  • Heterocyclic Compounds, 2-Ring / chemistry*
  • Heterocyclic Compounds, 2-Ring / pharmacology
  • Humans
  • Integrins / metabolism
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Molecular Probes / chemistry*
  • Molecular Probes / metabolism
  • Molecular Probes / pharmacology
  • Phosphorylation / drug effects
  • Protein Binding
  • Signal Transduction / drug effects
  • Structure-Activity Relationship
  • Thiourea / analogs & derivatives*
  • Thiourea / chemical synthesis
  • Thiourea / chemistry
  • Thiourea / pharmacology
  • U937 Cells
  • rab GTP-Binding Proteins / genetics
  • rab GTP-Binding Proteins / metabolism
  • rab7 GTP-Binding Proteins
  • ras Proteins / metabolism

Substances

  • CID1067700
  • Enzyme Inhibitors
  • Heterocyclic Compounds, 2-Ring
  • Integrins
  • Molecular Probes
  • rab7 GTP-Binding Proteins
  • EGFR protein, human
  • ErbB Receptors
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • GTP Phosphohydrolases
  • rab GTP-Binding Proteins
  • ras Proteins
  • Thiourea