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Identification of Inositol Phosphate or Phosphoinositide Interacting Proteins by Affinity Chromatography Coupled to Western Blot or Mass Spectrometry
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Multimodal action of KRP203 on phosphoinositide kinases in vitro and in cells

Yoshiki Ikeda1, Mindy I Davis2, Kazutaka Sumita3

  • 1Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA; Institute for Integrated Cell-Material Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan.

Biochemical and Biophysical Research Communications
|September 8, 2023
PubMed

Insights

The immunosuppressor KRP203/Mocravimod impacts phosphoinositide metabolism by affecting multiple enzymes. This multimodal activity offers a new therapeutic strategy for cancers linked to phosphoinositide signaling.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Cancer Research

Background:

  • Phosphoinositide signaling pathways are frequently dysregulated in cancer.
  • Traditional
  • one-drug, one-target
  • strategies have limitations in cancer therapy.
  • Targeting phosphoinositide metabolism offers a novel therapeutic avenue.

Purpose of the Study:

  • To investigate the effects of KRP203/Mocravimod on phosphoinositide metabolism.
  • To identify specific phosphoinositide kinases modulated by KRP203/Mocravimod.
  • To explore the potential of KRP203/Mocravimod as a multi-target therapeutic agent.

Main Methods:

  • High-throughput phosphatidylinositol 5-phosphate 4-kinase-alpha (PI5P4Kα) assay.
  • In vitro kinase activity assays for various phosphoinositide kinases.
  • Cellular analysis of phosphoinositide levels in U87MG glioblastoma cells following KRP203/Mocravimod treatment.

Main Results:

  • KRP203/Mocravimod significantly perturbs phosphoinositide metabolism in U87MG cells.
  • KRP203/Mocravimod exhibits differential effects, activating some kinases (e.g., PI5P4Kα, PI4KIIβ) and inhibiting others (e.g., PI5P4Kβ, γ, PI4KIIα).
  • Cellular treatment led to increased levels of PI(3)P, PI(5)P, PI(3,5)P2, and PI(3,4,5)P3.

Conclusions:

  • KRP203/Mocravimod demonstrates multimodal activity against multiple phosphoinositide kinases.
  • This compound modulates phosphoinositide metabolism through a novel mechanism.
  • The findings suggest a potential new therapeutic strategy for diseases involving aberrant phosphoinositide signaling.
Keywords:
Drug repurposingDrug screeningKRP203/MocravimodMulti targetsMultitarget drugOne drugPI3KPI3P5K/Type III PIPK/PIKFYVEPI5P4K/Type II PIPK/ phosphatidylinositol 5-phosphate 4-kinasePhosphoinositide metabolismPolypharmacology

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