title: Direct inhibition of the NOTCH transcription factor complex.
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 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.
authors.affiliation: Department of Chemistry & Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
authors.forename: Raymond E
authors.initials: RE
authors.lastname: Moellering
authors.forename: Melanie
authors.initials: M
authors.lastname: Cornejo
authors.forename: Tina N
authors.initials: TN
authors.lastname: Davis
authors.forename: Cristina
authors.initials: C
authors.lastname: Del Bianco
authors.forename: Jon C
authors.initials: JC
authors.lastname: Aster
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Blacklow
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Kung
authors.forename: D Gary
authors.initials: DG
authors.lastname: Gilliland
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Verdine
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000737:chemistry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016678:Genome / Q000187:drug effects / Q000235:genetics; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D009687:Nuclear Proteins / Q000737:chemistry; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013379:Substrate Specificity; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects*
chemical_list: D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; C430872:MAML1 protein, human; C497761:NOTCH1 protein, human; C497762:Notch1 protein, mouse; D009687:Nuclear Proteins; D010455:Peptides; C497570:RBPJ protein, human; D051881:Receptor, Notch1; D014157:Transcription Factors; C085316:mam protein, Drosophila