Direct inhibition of the NOTCH transcription factor complex.
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.
Moellering
Raymond E
RE
Department of Chemistry & Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
Cornejo
Melanie
M
Davis
Tina N
TN
Del Bianco
Cristina
C
Aster
Jon C
JC
Blacklow
Stephen C
SC
Kung
Andrew L
AL
Gilliland
D Gary
DG
Verdine
Gregory L
GL
Bradner
James E
JE
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*
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