Direct inhibition of the NOTCH transcription factor complex.
Nature, 2009/11/12;462(7270):182-8.
Moellering RE[1], Cornejo M, Davis TN, Del Bianco C, Aster JC, Blacklow SC, Kung AL, Gilliland DG, Verdine GL, Bradner JE
Affiliations
PMID: 19907488DOI: 10.1038/nature08543
Impact factor: 69.504
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.
MeSH terms
Animals; Binding, Competitive; Cell Line, Tumor; Cell Membrane Permeability; Cell Proliferation; DNA-Binding Proteins; Disease Models, Animal; Drosophila Proteins; Gene Expression Regulation, Neoplastic; Genome; Humans; Immunoglobulin J Recombination Signal Sequence-Binding Protein; Mice; Models, Molecular; Nuclear Proteins; Peptides; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Protein Binding; Protein Structure, Secondary; Protein Structure, Tertiary; Receptor, Notch1; Signal Transduction; Substrate Specificity; Transcription Factors; Transcriptional Activation
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