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
Titolo: | Direct Inhibition of the Notch Transcription Factor Complex |
Autori: | R. E., Moellering; M., Cornejo; T. N., Davis; Del Bianco, Cristina; J. C., Aster; S. C., Blacklow; A. L., Kung; D., Gary Gilliland; G. L., Verdine; J. E., Bradner |
Autori Unitn: | |
Titolo del periodico: | NATURE |
Anno di pubblicazione: | 2009 |
Codice identificativo Scopus: | 2-s2.0-70449671729 |
Codice identificativo Pubmed: | 19907488 |
Codice identificativo ISI: | WOS:000271655100035 |
Digital Object Identifier (DOI): | http://dx.doi.org/10.1038/nature08543 |
Handle: | http://hdl.handle.net/11572/96495 |
Appare nelle tipologie: | 03.1 Articolo su rivista (Journal article) |