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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
7270
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pubmed:dateCreated |
2009-11-12
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pubmed:databankReference |
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pubmed:abstractText |
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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pubmed:grant |
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pubmed:commentsCorrections |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Drosophila Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Immunoglobulin J Recombination...,
http://linkedlifedata.com/resource/pubmed/chemical/MAML1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/NOTCH1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Notch1 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Nuclear Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Peptides,
http://linkedlifedata.com/resource/pubmed/chemical/RBPJ protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Receptor, Notch1,
http://linkedlifedata.com/resource/pubmed/chemical/Transcription Factors,
http://linkedlifedata.com/resource/pubmed/chemical/mastermind protein, Drosophila
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pubmed:status |
MEDLINE
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pubmed:month |
Nov
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pubmed:issn |
1476-4687
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pubmed:author |
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pubmed:issnType |
Electronic
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pubmed:day |
12
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pubmed:volume |
462
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
182-8
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pubmed:dateRevised |
2011-3-29
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pubmed:meshHeading |
pubmed-meshheading:19907488-Animals,
pubmed-meshheading:19907488-Binding, Competitive,
pubmed-meshheading:19907488-Cell Line, Tumor,
pubmed-meshheading:19907488-Cell Membrane Permeability,
pubmed-meshheading:19907488-Cell Proliferation,
pubmed-meshheading:19907488-DNA-Binding Proteins,
pubmed-meshheading:19907488-Disease Models, Animal,
pubmed-meshheading:19907488-Drosophila Proteins,
pubmed-meshheading:19907488-Gene Expression Regulation, Neoplastic,
pubmed-meshheading:19907488-Genome,
pubmed-meshheading:19907488-Humans,
pubmed-meshheading:19907488-Immunoglobulin J Recombination Signal Sequence-Binding...,
pubmed-meshheading:19907488-Mice,
pubmed-meshheading:19907488-Models, Molecular,
pubmed-meshheading:19907488-Nuclear Proteins,
pubmed-meshheading:19907488-Peptides,
pubmed-meshheading:19907488-Precursor T-Cell Lymphoblastic Leukemia-Lymphoma,
pubmed-meshheading:19907488-Protein Binding,
pubmed-meshheading:19907488-Protein Structure, Secondary,
pubmed-meshheading:19907488-Protein Structure, Tertiary,
pubmed-meshheading:19907488-Receptor, Notch1,
pubmed-meshheading:19907488-Signal Transduction,
pubmed-meshheading:19907488-Substrate Specificity,
pubmed-meshheading:19907488-Transcription Factors,
pubmed-meshheading:19907488-Transcriptional Activation
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pubmed:year |
2009
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pubmed:articleTitle |
Direct inhibition of the NOTCH transcription factor complex.
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pubmed:affiliation |
Department of Chemistry & Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
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