Direct inhibition of the NOTCH transcription factor complex.

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.

Citation

Raymond E Moellering, Melanie Cornejo, Tina N Davis, Cristina Del Bianco, Jon C Aster, Stephen C Blacklow, Andrew L Kung, D Gary Gilliland, Gregory L Verdine, James E Bradner. Direct inhibition of the NOTCH transcription factor complex. Nature. 2009 Nov 12;462(7270):182-8

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PMID: 19907488

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