SMER28 Attenuates PI3K/mTOR Signaling by Direct Inhibition of PI3K p110 Delta

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Mechanism of Kemeng Fang's Inhibition of Podocyte Apoptosis in Rats with Membranous Nephropathy through the PI3K/AKT Signaling Pathway
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Marco Kirchenwitz1,2, Stephanie Stahnke1, Silvia Prettin1

  • 1Department of Cell Biology, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany.

Cells
|May 28, 2022
PubMed

Insights

Small molecule enhancer of Rapamycin 28 (SMER28) induces autophagy and inhibits receptor tyrosine kinase signaling by targeting PI3Kδ. This compound shows potential as a therapeutic for PI3Kδ-driven cancers.

Area of Science:

  • Cell Biology
  • Molecular Pharmacology
  • Cancer Biology

Background:

  • SMER28 is an autophagy-inducing compound with an unknown mechanism of action.
  • Autophagy plays a role in cellular homeostasis and disease.
  • Receptor tyrosine kinase (RTK) signaling is crucial for cell growth and survival.

Purpose of the Study:

  • To elucidate the mechanism of SMER28's autophagy induction.
  • To identify additional cellular effects of SMER28.
  • To evaluate SMER28 as a potential therapeutic agent.

Main Methods:

  • Assessment of autophagy-related parameters.
  • Cell cycle analysis.
  • Analysis of receptor tyrosine kinase signaling pathways.
  • Inhibition assays using PI3Kδ and p110γ.
  • Bacterial invasion assays using *Listeria monocytogenes* and *Salmonella* Typhimurium.
  • Apoptosis assays in B cell lymphoma and non-hematopoietic cells.

Main Results:

  • SMER28 confirmed to induce autophagy and cause growth retardation.
  • SMER28 completely arrested RTK signaling, inhibiting cell scattering and dorsal ruffles.
  • SMER28 directly inhibited PI3Kδ and p110γ, reducing PI3K downstream signaling.
  • SMER28 blocked *Listeria monocytogenes* entry, dependent on c-Met signaling, but not *Salmonella* Typhimurium entry.
  • SMER28 induced profound apoptosis in PI3Kδ-dependent B cell lymphoma cells.

Conclusions:

  • SMER28 functions by inhibiting PI3Kδ, leading to autophagy induction and RTK signaling arrest.
  • SMER28 exhibits anti-cancer potential, particularly in B cell malignancies dependent on PI3Kδ.
  • SMER28 is a promising drug candidate for diseases driven by aberrant PI3Kδ activity.
Keywords:
actinautophagycancer biologycell proliferationhepatocyte growth factor/scatter factor (HGF/SF)mammalian target of rapamycin (mTOR)phosphatidylinositol 3-kinase (PI 3-kinase)platelet-derived growth factor-C (PDGF-C)receptor tyrosine kinasesmall molecule

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