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EnglishDirect 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 Pubmed: | 19907488 |
| 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) |
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