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

Direct inhibition of the NOTCH transcription factor complex.

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  • 1Department of Chemistry & Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.

Erratum in

  • Nature. 2010 Jan 21;463(7279):384.

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.

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PMID:
19907488
[PubMed - indexed for MEDLINE]
PMCID:
PMC2951323
Free PMC Article

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