Direct inhibition of the NOTCH transcription factor complex

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 () and James E. Bradner ()
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Raymond E. Moellering: Harvard University, Cambridge, Massachusetts 02138, USA
Melanie Cornejo: Brigham & Women’s Hospital
Tina N. Davis: Dana-Farber Cancer Institute and Children’s Hospital
Cristina Del Bianco: Brigham & Women’s Hospital
Jon C. Aster: Brigham & Women’s Hospital
Stephen C. Blacklow: Brigham & Women’s Hospital
Andrew L. Kung: Dana-Farber Cancer Institute and Children’s Hospital
D. Gary Gilliland: Brigham & Women’s Hospital
Gregory L. Verdine: Harvard University, Cambridge, Massachusetts 02138, USA
James E. Bradner: Chemical Biology Program, Broad Institute of Harvard & MIT, Cambridge, Massachusetts 02142, USA

Nature, 2009, vol. 462, issue 7270, 182-188

Abstract: 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 α-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.

Date: 2009
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DOI: 10.1038/nature08543

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