The DOI matches its Crossref record; 51 of the 51 references it cites were found in a registry or an index.
Direct inhibition of the NOTCH transcription factor complex
Open accessAbstract
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506580102 · Cited by 53,625
Notch Signaling: Cell Fate Control and Signal Integration in Development
Artavanis-Tsakonas, S., Rand, M. D., & Lake, R. J. (1999) · Science · doi:10.1126/science.284.5415.770 · Cited by 5,909
Lamb, J., Crawford, E. D., Peck, D., Modell, J. W., Blat, I. C., Wrobel, M. J., Lerner, J., Brunet, J.-P., Subramanian, A., Ross, K. N., et al. (2006) · Science · doi:10.1126/science.1132939 · Cited by 5,257
Activating Mutations of NOTCH1 in Human T Cell Acute Lymphoblastic Leukemia
Weng, A. P., Ferrando, A. A., Lee, W., Morris, J. P., Silverman, L. B., Sanchez-Irizarry, C., Blacklow, S. C., Look, A. T., & Aster, J. C. (2004) · Science · doi:10.1126/science.1102160 · Cited by 2,706
Self-citationNotch signalling: a simple pathway becomes complex
Bray, S. J. (2006) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2009 · Cited by 2,620
A presenilin-1-dependent γ-secretase-like protease mediates release of Notch intracellular domain
De Strooper, B., Annaert, W., Cupers, P., Saftig, P., Craessaerts, K., Mumm, J. S., Schroeter, E. H., Schrijvers, V., Wolfe, M. S., Ray, W. J., et al. (1999) · Nature · doi:10.1038/19083 · Cited by 2,100
Determination of the helix and β form of proteins in aqueous solution by circular dichroism
Chen, Y.-H., Yang, J. T., & Chau, K. H. (1974) · Biochemistry · doi:10.1021/bi00713a027 · Cited by 2,070
Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia
Joutel, A., Corpechot, C., Ducros, A., Vahedi, K., Chabriat, H., Mouton, P., Alamowitch, S., Domenga, V., Cécillion, M., Maréchal, E., et al. (1996) · Nature · doi:10.1038/383707a0 · Cited by 2,068
Ellisen, L. W., Bird, J., West, D. C., Soreng, A. L., Reynolds, T. C., Smith, S. D., & Sklar, J. (1991) · Cell · doi:10.1016/0092-8674(91)90111-b · Cited by 1,691
Mutations in NOTCH1 cause aortic valve disease
Garg, V., Muth, A. N., Ransom, J. F., Schluterman, M. K., Barnes, R., King, I. N., Grossfeld, P. D., & Srivastava, D. (2005) · Nature · doi:10.1038/nature03940 · Cited by 1,509
Activation of Apoptosis in Vivo by a Hydrocarbon-Stapled BH3 Helix
Walensky, L. D., Kung, A. L., Escher, I., Malia, T. J., Barbuto, S., Wright, R. D., Wagner, G., Verdine, G. L., & Korsmeyer, S. J. (2004) · Science · doi:10.1126/science.1099191 · Cited by 1,349
Self-citationAlagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1
Li, L., Krantz, I. D., Deng, Y., Genin, A., Banta, A. B., Collins, C. C., Qi, M., Trask, B. J., Kuo, W. L., Cochran, J., et al. (1997) · Nature Genetics · doi:10.1038/ng0797-243 · Cited by 1,281
Transcription factors as targets for cancer therapy
Darnell, J. E. (2002) · Nature Reviews Cancer · doi:10.1038/nrc906 · Cited by 1,194
Schafmeister, C. E., Po, J., & Verdine, G. L. (2000) · Journal of the American Chemical Society · doi:10.1021/ja000563a · Cited by 1,037
Self-citationNotch1 functions as a tumor suppressor in mouse skin
Nicolas, M., Wolfer, A., Raj, K., Kummer, J. A., Mill, P., van Noort, M., Hui, C., Clevers, H. C., Dotto, G. P., & Radtke, F. (2003) · Nature Genetics · doi:10.1038/ng1099 · Cited by 969
Notch signals control the fate of immature progenitor cells in the intestine
Fré, S., Huyghe, M., Mourikis, P., Robine, S., Louvard, D., & Artavanis‐Tsakonas, S. (2005) · Nature · doi:10.1038/nature03589 · Cited by 936
Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia
Palomero, T., Sulis, M. L., Cortina, M. S., Real, P. J., Barnes, K., Ciofani, M., Caparrós, E., Buteau, J., Brown, K. R., Perkins, S. L., et al. (2007) · Nature Medicine · doi:10.1038/nm1636 · Cited by 876
Functional gamma‐secretase inhibitors reduce beta‐amyloid peptide levels in brain
Dovey, H. F., John, V., Anderson, J. P., Chen, L. Z., Andrieu, P. D. S. I., Fang, L. Y., Freedman, S. B., Folmer, B., Goldbach, E. G., Holsztynska, E. J., et al. (2001) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2001.00012.x · Cited by 870
c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphomaPreprint
Weng, A. P., Millholland, J. M., Yashiro–Ohtani, Y., Arcangeli, M.-L., Lau, A. N., Wai, C., Bianco, C. D., Rodríguez, C. G., Sai, H., Tobias, J. W., et al. (2006) · Genes & Development · doi:10.1101/gad.1450406 · Cited by 863
Self-citationPalomero, T., Lim, W. K., Odom, D. T., Sulis, M. L., Real, P. J., Margolin, A. A., Barnes, K., O’Neil, J., Neuberg, D. S., Weng, A. P., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0606108103 · Cited by 821
Self-citationPresenilin is required for activity and nuclear access of Notch in Drosophila
Struhl, G., & Greenwald, I. (1999) · Nature · doi:10.1038/19091 · Cited by 804
O’Neil, J., Grim, J. A., Strack, P. R., Rao, S. S., Tibbitts, D., Winter, C. G., Hardwick, J. S., Welcker, M., Meijerink, J. P. P., Pieters, R., et al. (2007) · The Journal of Experimental Medicine · doi:10.1084/jem.20070876 · Cited by 681
Notch mediates TGFα-induced changes in epithelial differentiation during pancreatic tumorigenesis
Miyamoto, Y., Maitra, A., Ghosh, B., Zechner, U., Argani, P., Iacobuzio-Donahue, C. A., Sriuranpong, V., Iso, T., Meszoely, I. M., Wolfe, M. S., et al. (2003) · Cancer Cell · doi:10.1016/s1535-6108(03)00140-5 · Cited by 643
Wu, L., Aster, J. C., Blacklow, S. C., Lake, R., Artavanis‐Tsakonas, S., & Griffin, J. D. (2000) · Nature Genetics · doi:10.1038/82644 · Cited by 579
Self-citationThe suppressor of hairless protein participates in notch receptor signaling
Fortini, M. (1994) · Cell · doi:10.1016/0092-8674(94)90196-1 · Cited by 541
Neurogenic phenotypes and altered Notch processing in Drosophila Presenilin mutants
Ye, Y., Lukinova, N. I., & Fortini, M. (1999) · Nature · doi:10.1038/19096 · Cited by 492
Notch4/int-3, a mammary proto-oncogene, is an endothelial cell-specific mammalian Notch gene
Uyttendaele, H., Marazzi, G., Wu, G., Yan, Q., Sassoon, D. A., & Kitajewski, J. (1996) · Development · doi:10.1242/dev.122.7.2251 · Cited by 490
Loss of negative regulation by Numb over Notch is relevant to human breast carcinogenesis
Pece, S., Serresi, M., Santolini, E., Capra, M. C., Hulleman, E., Galimberti, V. E., Zurrida, S., Maisonneuve, P., Viale, G., & Fiore, P. P. D. (2004) · The Journal of Cell Biology · doi:10.1083/jcb.200406140 · Cited by 483
Nam, Y., Piotr Sliz, A., Song, L., Aster, J. C., & Blacklow, S. C. (2006) · Cell · doi:10.1016/j.cell.2005.12.037 · Cited by 459
Self-citationγ-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia
Real, P. J., Tosello, V., Palomero, T., Castillo-Martín, M., Hernando, E., de Stanchina, E., Sulis, M. L., Barnes, K., Sawai, C. M., Homminga, I., et al. (2008) · Nature Medicine · doi:10.1038/nm.1900 · Cited by 445
Riccio, O., van Gijn, M. E., Bezdek, A. C., Pellegrinet, L., van Es, J. H., Zimber‐Strobl, U., Strobl, L. J., Honjo, T., Clevers, H. C., & Radtke, F. (2008) · EMBO Reports · doi:10.1038/embor.2008.7 · Cited by 411
Crystal Structure of the CSL-Notch-Mastermind Ternary Complex Bound to DNA
Wilson, J. J., & Kovall, R. A. (2006) · Cell · doi:10.1016/j.cell.2006.01.035 · Cited by 371
Growth Suppression of Pre-T Acute Lymphoblastic Leukemia Cells by Inhibition of Notch Signaling
Weng, A. P., Nam, Y., Wolfe, M. S., Pear, W. S., Griffin, J. D., Blacklow, S. C., & Aster, J. C. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.2.655-664.2003 · Cited by 369
Self-citationPresenilin-1 and -2 Are Molecular Targets for γ-Secretase Inhibitors
Seiffert, D., Bradley, J. D., Rominger, C. M., Rominger, D. H., Yang, F., Meredith, J. E., Wang, Q., Roach, A., Thompson, L. A., Spitz, S. M., et al. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m005430200 · Cited by 301
Mastermind critically regulates Notch-mediated lymphoid cell fate decisions
Maillard, I. P., Weng, A. P., Carpenter, A. C., Rodríguez, C. G., Sai, H., Xu, L., Allman, D., Aster, J. C., & Pear, W. S. (2004) · Blood · doi:10.1182/blood-2004-02-0514 · Cited by 284
Self-citationAster, J. C., Xu, L., Karnell, F. G., Patriub, V., Pui, J. C., & Pear, W. S. (2000) · Molecular and Cellular Biology · doi:10.1128/mcb.20.20.7505-7515.2000 · Cited by 278
Self-citationNefedova, Y., Cheng, P., Alsina, M., Dalton, W. S., & Gabrilovich, D. I. (2003) · Blood · doi:10.1182/blood-2003-07-2340 · Cited by 270
Notch3 Gene Amplification in Ovarian Cancer
Park, J. T., Li, M., Nakayama, K., Mao, T., Davidson, B., Zhang, Z., Kurman, R. J., Eberhart, C. G., Shih, I., & Wang, T. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-3610 · Cited by 258
γ-Secretase Inhibitor Prevents Notch3 Activation and Reduces Proliferation in Human Lung Cancers
Konishi, J. S., Kawaguchi, K. S., Vo, H., Haruki, N., González, A., Carbone, D. P., & Dang, T. P. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-1022 · Cited by 253
Leukemia-associated NOTCH1 alleles are weak tumor initiators but accelerate K-ras–initiated leukemia
Chiang, M. Y., Xu, L., Shestova, O. E., Histen, G., L’Heureux, S., Romany, C. A., Childs, M. E., Gimotty, P. A., Aster, J. C., & Pear, W. S. (2008) · Journal of Clinical Investigation · doi:10.1172/jci35090 · Cited by 235
Self-citationWilliams, R. M., & IM, M. ‐. (1991) · Journal of the American Chemical Society · doi:10.1021/ja00024a038 · Cited by 204
Nam, Y., Weng, A. P., Aster, J. C., & Blacklow, S. C. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m301567200 · Cited by 201
Self-citationMastermind is a putative activator for Notch
Petcherski, A. G., & Kimble, J. E. (2000) · Current Biology · doi:10.1016/s0960-9822(00)00577-7 · Cited by 183
Rao, S. S., O’Neil, J., Liberator, C. D., Hardwick, J. S., Dai, X., Zhang, T., Tyminski, E., Yuan, J., Kohl, N. E., Richon, V. M., et al. (2009) · Cancer Research · doi:10.1158/0008-5472.can-08-4295 · Cited by 153
Lewis, H. D., Leveridge, M., Strack, P. R., Haldon, C., O’Neil, J., Kim, H., Madin, A., Hannam, J. C., Look, A. T., Kohl, N. E., et al. (2007) · Chemistry & Biology · doi:10.1016/j.chembiol.2006.12.010 · Cited by 147
Stubbs, M. C., Kim, Y., Krivtsov, A. V., Wright, R. D., Feng, Z., Agarwal, J., Kung, A. L., & Armstrong, S. A. (2007) · Leukemia · doi:10.1038/sj.leu.2404951 · Cited by 115
Self-citationA Novel Noninvasive Model of Endometriosis for Monitoring the Efficacy of Antiangiogenic Therapy
Becker, C. M., Wright, R. D., Satchi‐Fainaro, R., Funakoshi, T., Folkman, J., Kung, A. L., & D’Amato, R. J. (2006) · American Journal Of Pathology · doi:10.2353/ajpath.2006.051133 · Cited by 84
Self-citationActivity of γ -Secretase on Substrates Other than APP
Alberto, D. (2008) · Current Topics in Medicinal Chemistry · doi:10.2174/156802608783334060 · Cited by 67
Mutational and Energetic Studies of Notch1 Transcription Complexes
Bianco, C. D., Aster, J. C., & Blacklow, S. C. (2007) · Journal of Molecular Biology · doi:10.1016/j.jmb.2007.11.061 · Cited by 57
Self-citationHallis, T. M., Kopp, A. L., Gibson, J. R., Lebakken, C. S., Hancock, M. K., VanDenHeuvel-Kramer, K., & Turek-Etienne, T. C. (2007) · SLAS DISCOVERY · doi:10.1177/1087057107301499 · Cited by 15
Williams, R. M., & IM, M. ‐. (1992) · ChemInform · doi:10.1002/chin.199212255 · Cited by 8
Flagged first, then by citations
Cited by
Sorted by citations
Overcoming the challenges in administering biopharmaceuticals: Formulation and delivery strategies
Mitragotri, S., Burke, P. A., & Langer, R. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4363 · Cited by 1,702
Transcriptional Addiction in Cancer
Bradner, J. E., Hnisz, D., & Young, R. A. (2017) · Cell · doi:10.1016/j.cell.2016.12.013 · Cited by 1,221
Self-citationTargeting cancer stem cells by inhibiting Wnt, Notch, and Hedgehog pathways
Takebe, N., Harris, P. J., Warren, R. Q., & Ivy, S. P. (2010) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2010.196 · Cited by 1,025
Notch Signaling in Development, Tissue Homeostasis, and Disease
Siebel, C., & Lendahl, U. (2017) · Physiological Reviews · doi:10.1152/physrev.00005.2017 · Cited by 1,001
Notch signaling: simplicity in design, versatility in function
Andersson, E. R., Sandberg, R., & Lendahl, U. (2011) · Development · doi:10.1242/dev.063610 · Cited by 950
Metadata
- Authors
- Moellering, R. E., Cornejo, M., Davis, T. N., Bianco, C. D., Aster, J. C., Blacklow, S. C., Kung, A. L., Gilliland, D. G., Verdine, G. L., & Bradner, J. E.
- Affiliations
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- Dana-Farber Cancer Institute (US)
- Harvard University (US)
- Corresponding author
- Verdine, Gregory L.
- Bradner, James E.
- ORCID
- Venue
- Nature
- Published
- 2009-11-12
- Volume
- 462
- Issue
- 7270
- Pages
- 182-188
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2951323
- OpenAlex
- W2085948054
- Cited by
- 752
- References
- 51
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 12 · 2023: 30 · 2022: 21 · 2021: 28 · 2020: 43 · 2019: 35 · 2018: 47 · 2017: 43 · 2016: 34 · 2015: 56 · 2014: 70 · 2013: 76 · 2012: 75
- FWCI
- 32.31
- Type
- journal article
- Language
- en
- Update notices
- erratum (2010-01-21)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Iris (University of Trento) (submittedVersion)
- Funders
- National Institutes of Health (n01co12400-79-0-22, 5t32gm007598-41)
- National Cancer Institute (N01CO12400, N01-CO-012400, P01CA119070, R01CA092433, R56CA092433)
- National Institute of General Medical Sciences (5T32GM007598, T32-GM007598)
- Topics
- Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- Notch signaling, hydrocarbon-stapled peptides, protein-protein interaction inhibition, T-cell acute lymphoblastic leukemia, Notch1, transcription factor antagonism, cell-permeable peptide
- MeSH terms
- Animals, Binding, Competitive, Cell Membrane Permeability, Disease Models, Animal, DNA-Binding Proteins, Humans, Models, Molecular, Nuclear Proteins, Peptides, Protein Binding, Substrate Specificity, Transcription Factors, Signal Transduction, Transcriptional Activation, Gene Expression Regulation, Neoplastic, Genome, Protein Structure, Secondary, Protein Structure, Tertiary, Drosophila Proteins, Cell Line, Tumor, Cell Proliferation, Mice, Immunoglobulin J Recombination Signal Sequence-Binding Protein, Receptor, Notch1, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
