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Phosphoinositides and PIPs01:42

Phosphoinositides and PIPs

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Phosphoinositides are a group of phospholipids containing a glycerol backbone with two fatty acid chains and a phosphate attached to a myoinositol sugar ring. The inositol head group extends into the cytoplasm, where it is modified by adding phosphate groups to form phosphatidylinositol phosphates or PIPs.
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A Pipeline to Investigate the Structures and Signaling Pathways of Sphingosine 1-Phosphate Receptors
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Sphingosine Kinase 2 Inhibitors: Rigid Aliphatic Tail Derivatives Deliver Potent and Selective Analogues.

Srinath Pashikanti1,2, Daniel J Foster1, Yugesh Kharel3

  • 1Department of Chemistry, Virginia Tech, Blacksburg, Virginia 24060, United States.

ACS Bio & Med Chem Au
|October 25, 2022
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Summary

Researchers developed novel sphingosine kinase 2 (SphK2) inhibitors by rigidifying the lipid tail. Compound 14c potently inhibits SphK2, reduces extracellular S1P, and engages the target in vivo.

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Area of Science:

  • Biochemistry
  • Medicinal Chemistry
  • Pharmacology

Background:

  • Sphingosine 1-phosphate (S1P) is a signaling molecule regulating cell functions via G-protein coupled receptors (S1P1-5).
  • Sphingosine kinases (SphK1 and SphK2) are key enzymes in S1P synthesis and are targeted for therapeutic intervention in diseases like cancer and multiple sclerosis.

Purpose of the Study:

  • To design, synthesize, and evaluate novel sphingosine kinase 2 (SphK2) inhibitors.
  • To explore the impact of rigid structures in the aliphatic lipid tail on SphK2 inhibition.

Main Methods:

  • Systematic structural modification of existing SphK2 inhibitors to introduce rigidity.
  • Molecular modeling and docking studies to understand ligand-protein interactions.
  • In vitro enzymatic assays to determine inhibitor potency and selectivity (e.g., Ki values).
  • Cell-based assays using U937 cells to measure extracellular S1P levels.
  • In vivo studies in mice to assess target engagement and S1P pharmacokinetics.

Main Results:

  • Identification of compound 14c (SLP9101555) as a potent SphK2 inhibitor with a Ki of 90 nM.
  • Compound 14c demonstrated over 200-fold selectivity for SphK2 compared to SphK1.
  • Molecular docking revealed key binding interactions, including a cyclohexyl ring in a deep cleft and a guanidino group forming a hydrogen bond with Asp308.
  • In vitro studies showed that SphK2 inhibitors significantly reduced extracellular S1P levels in U937 cells.
  • In vivo administration of 14c to mice led to sustained increases in circulating S1P levels, indicating target engagement.

Conclusions:

  • Conformationally restricted analogues with rigid lipophilic tails are effective for targeting the SphK2 binding pocket.
  • Compound 14c is a potent and selective SphK2 inhibitor with demonstrated target engagement in vitro and in vivo.
  • These findings support SphK2 as a viable therapeutic target and provide promising lead compounds for drug development.