Development of a peptide-based inducer of protein degradation targeting NOTCH1

Bioorg Med Chem Lett. 2017 Nov 15;27(22):4985-4988. doi: 10.1016/j.bmcl.2017.10.011. Epub 2017 Oct 7.

Abstract

We previously developed a protein knockdown system by small-molecule hybrid compounds named SNIPERs (Specific and Nongenetic IAP-dependent Protein Erasers). Here we report a peptide-based protein knockdown system for inducing degradation of a transcriptional factor NOTCH1. The molecules designed were composed of two biologically active scaffolds: a peptide that binds to the surface of the target protein NOTCH1 and a small-molecule MV1 that binds to the E3 ubiquitin ligase inhibitor of apoptosis protein (IAP), which are expected to cross-link these proteins in cells. Hybrid molecules specifically induced the degradation of the NOTCH1 protein by the proteasome. This system could be a useful method to develop various degradation inducers against a large number of proteins to which small-molecule ligands have not been found.

Keywords: NOTCH1; Proteasome; Protein knockdown; Transcriptional factor; Ubiquitin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Binding Sites
  • Cell Line, Tumor
  • Crystallography, X-Ray
  • Humans
  • Inhibitor of Apoptosis Proteins / antagonists & inhibitors
  • Inhibitor of Apoptosis Proteins / metabolism
  • Ligands
  • Molecular Docking Simulation
  • Peptides / chemistry
  • Peptides / metabolism*
  • Protein Structure, Tertiary
  • Proteolysis*
  • Receptor, Notch1 / chemistry
  • Receptor, Notch1 / metabolism*
  • Transcription Factors / chemistry
  • Transcription Factors / metabolism
  • Ubiquitin-Protein Ligases / chemistry
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • Inhibitor of Apoptosis Proteins
  • Ligands
  • Peptides
  • Receptor, Notch1
  • Transcription Factors
  • Ubiquitin-Protein Ligases