Publication Date:
2009-11-13
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2951323/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2951323/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Moellering, Raymond E -- Cornejo, Melanie -- Davis, Tina N -- Del Bianco, Cristina -- Aster, Jon C -- Blacklow, Stephen C -- Kung, Andrew L -- Gilliland, D Gary -- Verdine, Gregory L -- Bradner, James E -- 5T32GM007598/GM/NIGMS NIH HHS/ -- N01-CO-12400/CO/NCI NIH HHS/ -- P01 CA119070/CA/NCI NIH HHS/ -- P01 CA119070-049001/CA/NCI NIH HHS/ -- R01 CA092433/CA/NCI NIH HHS/ -- R01 CA092433-06A2/CA/NCI NIH HHS/ -- R56 CA092433/CA/NCI NIH HHS/ -- R56 CA092433-06A1/CA/NCI NIH HHS/ -- T32 GM007598/GM/NIGMS NIH HHS/ -- T32 GM007598-30/GM/NIGMS NIH HHS/ -- England -- Nature. 2009 Nov 12;462(7270):182-8. doi: 10.1038/nature08543.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry & Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19907488" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Binding, Competitive
;
Cell Line, Tumor
;
Cell Membrane Permeability
;
Cell Proliferation/drug effects
;
DNA-Binding Proteins/chemistry/metabolism
;
Disease Models, Animal
;
Drosophila Proteins/chemistry
;
Gene Expression Regulation, Neoplastic/drug effects
;
Genome/drug effects/genetics
;
Humans
;
Immunoglobulin J Recombination Signal Sequence-Binding Protein/metabolism
;
Mice
;
Models, Molecular
;
Nuclear Proteins/chemistry
;
Peptides/chemical synthesis/chemistry/metabolism/*pharmacology
;
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy/genetics/pathology
;
Protein Binding/drug effects
;
Protein Structure, Secondary
;
Protein Structure, Tertiary
;
Receptor, Notch1/*antagonists & inhibitors/chemistry/metabolism
;
Signal Transduction/drug effects
;
Substrate Specificity
;
Transcription Factors/chemistry/metabolism
;
Transcriptional Activation/*drug effects
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
