Novel all-hydrocarbon stapled p110α[E545K] peptides as blockers of the oncogenic p110α[E545K]-IRS1 interaction

Bioorg Med Chem Lett. 2017 Dec 15;27(24):5446-5449. doi: 10.1016/j.bmcl.2017.10.076. Epub 2017 Nov 12.

Abstract

To follow up on our recent discovery of the 18-amino acid all-hydrocarbon [i, i + 4]-stapled p110α[E545K] peptide 1 that was shown to potently block the intracellular p110α[E545K]-IRS1 interaction (a protein-protein interaction uniquely present in cancer cells expressing p110α[E545K]) and the growth of the xenograft tumors formed by cancers harboring this mutation, in the current study we prepared and examined six derivatives of 1, i.e. stapled peptides 2-A, 2-B, 3-A, 3-B, 4-A, 4-B. We found that 2-A, 2-B, 4-A, and 4-B had higher % α-helicity than 1; moreover, the enhanced % α-helicity also led to an enhanced proteolytic stability. When compared with 1, the structurally simplified 14-amino acid 4-A and 4-B were found to more potently deactivate the AKT phosphorylation at Ser473 in the p110α[E545K]-expressing colon cancer cells, whose activation was previously demonstrated by us to be specifically derived from the p110α[E545K]-IRS1 interaction. The preliminary findings from the current study have laid a foundation for future more extensive studies on the stapled p110α[E545K] peptides newly identified in the current study.

Keywords: % α-helicity; AKT phosphorylation; Anti-cancer therapeutic; IRS1; Protein-protein interaction; Proteolytic stability; Stapled peptide; p110α[E545K].

Publication types

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

MeSH terms

  • Cell Line, Tumor
  • Circular Dichroism
  • Class I Phosphatidylinositol 3-Kinases / antagonists & inhibitors
  • Class I Phosphatidylinositol 3-Kinases / genetics
  • Class I Phosphatidylinositol 3-Kinases / metabolism*
  • Humans
  • Hydrocarbons / chemistry*
  • Insulin Receptor Substrate Proteins / antagonists & inhibitors
  • Insulin Receptor Substrate Proteins / metabolism*
  • Mutation
  • Nuclear Magnetic Resonance, Biomolecular
  • Peptides / chemical synthesis
  • Peptides / chemistry*
  • Peptides / pharmacology
  • Phosphorylation / drug effects
  • Protein Interaction Maps / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism

Substances

  • Hydrocarbons
  • Insulin Receptor Substrate Proteins
  • Peptides
  • Class I Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt