Direct Inhibition of the NOTCH Transcription Factor Complex

Nature. 2009 Nov 12;462(7270):182-8. doi: 10.1038/nature08543.

Abstract

Direct inhibition of transcription factor complexes remains a central challenge in the discipline of ligand discovery. In general, these proteins lack surface involutions suitable for high-affinity binding by small molecules. Here we report the design of synthetic, cell-permeable, stabilized alpha-helical peptides that target a critical protein-protein interface in the NOTCH transactivation complex. We demonstrate that direct, high-affinity binding of the hydrocarbon-stapled peptide SAHM1 prevents assembly of the active transcriptional complex. Inappropriate NOTCH activation is directly implicated in the pathogenesis of several disease states, including T-cell acute lymphoblastic leukaemia (T-ALL). The treatment of leukaemic cells with SAHM1 results in genome-wide suppression of NOTCH-activated genes. Direct antagonism of the NOTCH transcriptional program causes potent, NOTCH-specific anti-proliferative effects in cultured cells and in a mouse model of NOTCH1-driven T-ALL.

Publication types

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

MeSH terms

  • Animals
  • Binding, Competitive
  • Cell Line, Tumor
  • Cell Membrane Permeability
  • Cell Proliferation / drug effects
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / metabolism
  • Disease Models, Animal
  • Drosophila Proteins / chemistry
  • Gene Expression Regulation, Neoplastic / drug effects
  • Genome / drug effects
  • Genome / genetics
  • Humans
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein / metabolism
  • Mice
  • Models, Molecular
  • Nuclear Proteins / chemistry
  • Peptides / chemical synthesis
  • Peptides / chemistry
  • Peptides / metabolism
  • Peptides / pharmacology*
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • Protein Binding / drug effects
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Receptor, Notch1 / antagonists & inhibitors*
  • Receptor, Notch1 / chemistry
  • Receptor, Notch1 / metabolism
  • Signal Transduction / drug effects
  • Substrate Specificity
  • Transcription Factors / chemistry
  • Transcription Factors / metabolism
  • Transcriptional Activation / drug effects*

Substances

  • DNA-Binding Proteins
  • Drosophila Proteins
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein
  • MAML1 protein, human
  • NOTCH1 protein, human
  • Notch1 protein, mouse
  • Nuclear Proteins
  • Peptides
  • RBPJ protein, human
  • Receptor, Notch1
  • Transcription Factors
  • mam protein, Drosophila

Associated data

  • GEO/GSE18198
  • GEO/GSE18351