PMID- 19907488
OWN - NLM
STAT- MEDLINE
DCOM- 20100105
LR  - 20220318
IS  - 1476-4687 (Electronic)
IS  - 0028-0836 (Print)
IS  - 0028-0836 (Linking)
VI  - 462
IP  - 7270
DP  - 2009 Nov 12
TI  - Direct inhibition of the NOTCH transcription factor complex.
PG  - 182-8
LID - 10.1038/nature08543 [doi]
AB  - 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.
FAU - Moellering, Raymond E
AU  - Moellering RE
AD  - Department of Chemistry & Chemical Biology, Harvard University, Cambridge, 
      Massachusetts 02138, USA.
FAU - Cornejo, Melanie
AU  - Cornejo M
FAU - Davis, Tina N
AU  - Davis TN
FAU - Del Bianco, Cristina
AU  - Del Bianco C
FAU - Aster, Jon C
AU  - Aster JC
FAU - Blacklow, Stephen C
AU  - Blacklow SC
FAU - Kung, Andrew L
AU  - Kung AL
FAU - Gilliland, D Gary
AU  - Gilliland DG
FAU - Verdine, Gregory L
AU  - Verdine GL
FAU - Bradner, James E
AU  - Bradner JE
LA  - eng
SI  - GEO/GSE18198
SI  - GEO/GSE18351
GR  - R56 CA092433/CA/NCI NIH HHS/United States
GR  - R56 CA092433-06A1/CA/NCI NIH HHS/United States
GR  - 5T32GM007598/GM/NIGMS NIH HHS/United States
GR  - N01CO12400/CA/NCI NIH HHS/United States
GR  - R01 CA092433-06A2/CA/NCI NIH HHS/United States
GR  - N01-CO-12400/CO/NCI NIH HHS/United States
GR  - P01 CA119070/CA/NCI NIH HHS/United States
GR  - R01 CA092433/CA/NCI NIH HHS/United States
GR  - T32 GM007598/GM/NIGMS NIH HHS/United States
GR  - P01 CA119070-049001/CA/NCI NIH HHS/United States
GR  - T32 GM007598-30/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Nature
JT  - Nature
JID - 0410462
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Drosophila Proteins)
RN  - 0 (Immunoglobulin J Recombination Signal Sequence-Binding Protein)
RN  - 0 (MAML1 protein, human)
RN  - 0 (NOTCH1 protein, human)
RN  - 0 (Notch1 protein, mouse)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Peptides)
RN  - 0 (RBPJ protein, human)
RN  - 0 (Receptor, Notch1)
RN  - 0 (Transcription Factors)
RN  - 0 (mam protein, Drosophila)
SB  - IM
EIN - Nature. 2010 Jan 21;463(7279):384
CIN - Nature. 2009 Nov 12;462(7270):171-3. PMID: 19907487
MH  - Animals
MH  - Binding, Competitive
MH  - Cell Line, Tumor
MH  - Cell Membrane Permeability
MH  - Cell Proliferation/drug effects
MH  - DNA-Binding Proteins/chemistry/metabolism
MH  - Disease Models, Animal
MH  - Drosophila Proteins/chemistry
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - Genome/drug effects/genetics
MH  - Humans
MH  - Immunoglobulin J Recombination Signal Sequence-Binding Protein/metabolism
MH  - Mice
MH  - Models, Molecular
MH  - Nuclear Proteins/chemistry
MH  - Peptides/chemical synthesis/chemistry/metabolism/*pharmacology
MH  - Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy/genetics/pathology
MH  - Protein Binding/drug effects
MH  - Protein Structure, Secondary
MH  - Protein Structure, Tertiary
MH  - Receptor, Notch1/*antagonists & inhibitors/chemistry/metabolism
MH  - Signal Transduction/drug effects
MH  - Substrate Specificity
MH  - Transcription Factors/chemistry/metabolism
MH  - Transcriptional Activation/*drug effects
PMC - PMC2951323
MID - NIHMS186490
EDAT- 2009/11/13 06:00
MHDA- 2010/01/06 06:00
PMCR- 2010/10/07
CRDT- 2009/11/13 06:00
PHST- 2009/01/29 00:00 [received]
PHST- 2009/09/25 00:00 [accepted]
PHST- 2009/11/13 06:00 [entrez]
PHST- 2009/11/13 06:00 [pubmed]
PHST- 2010/01/06 06:00 [medline]
PHST- 2010/10/07 00:00 [pmc-release]
AID - nature08543 [pii]
AID - 10.1038/nature08543 [doi]
PST - ppublish
SO  - Nature. 2009 Nov 12;462(7270):182-8. doi: 10.1038/nature08543.