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 α-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

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Article 01 September 2022 STRUCTURAL INSIGHTS INTO HUMAN BRACHYURY DNA RECOGNITION AND DISCOVERY OF PROGRESSIBLE BINDERS FOR CANCER THERAPY Article Open access 14 February 2025 SELECTIVE

INHIBITION OF STAT3 SIGNALING USING MONOBODIES TARGETING THE COILED-COIL AND N-TERMINAL DOMAINS Article Open access 17 August 2020 ACCESSION CODES PRIMARY ACCESSIONS GENE EXPRESSION OMNIBUS

* GSE18198 * GSE18351 PROTEIN DATA BANK * 2F8X DATA DEPOSITS All microarray data has been deposited to the Gene Expression Omnibus at the National Center for Biotechnology Information under

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Schreiber and the Broad Institute Chemical Biology Program for discussions and access to instrumentation; J. Rocnik for assistance in the establishment of the T-ALL murine model; A. Ferrando

for providing GSI microarray data; M. Hancock and Invitrogen for providing β-lactamase HeLa reporter clones; K. Ross and A. Subramanian for conversations and guidance about GSEA; and S.

Gupta and the Broad Institute Microarray Core. This work was supported by a Specialized Center of Research grant from the Leukaemia & Lymphoma Society (to J.E.B., J.C.A., S.C.B.), an

AACR Centennial Pre-doctoral Research Fellowship in Cancer Research (to R.E.M.), the American Society of Hematology (to J.E.B.), MCCB-NIH Training Grant No. 5T32GM007598 (to R.E.M.), the

Human Frontier Science Program (to C.D.), and the Harvard & Dana Farber Program in Cancer Chemical Biology (to J.E.B., R.E.M., G.L.V.). The project has been funded in part with Federal

funds from the National Cancer Institute’s Initiative for Chemical Genetics, National Institutes of Health, under Contract No. N01-CO-12400. Histology and immunohistochemical staining was

performed in the Dana Farber/Harvard Cancer Center Specialized Histopathology Services Core Laboratory. AUTHOR CONTRIBUTIONS R.E.M., G.L.V. and J.E.B. conceptualized the study, designed the

experiments, interpreted data, and wrote the manuscript. Design, synthesis and biological characterization of SAHM peptides was performed by R.E.M. C.D.B., J.C.A. and S.C.B. contributed key

reagents and analysed data. R.E.M., M.C., T.N.D., J.C.A., A.L.K., D.G.G. and J.E.B. established the bioluminescent T-ALL model, designed and performed _in vivo_ experiments and analysed

data. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Chemistry & Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA, Raymond E. Moellering & 

Gregory L. Verdine * Chemical Biology Program, Broad Institute of Harvard & MIT, Cambridge, Massachusetts 02142, USA, Raymond E. Moellering & James E. Bradner * Program in Cancer

Chemical Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA, Raymond E. Moellering, Gregory L. Verdine & James E. Bradner * Division of Hematology, Brigham &

Women’s Hospital, Melanie Cornejo & D. Gary Gilliland * Department of Pathology, Brigham & Women’s Hospital, Cristina Del Bianco, Jon C. Aster & Stephen C. Blacklow * Department

of Pediatric Oncology, Dana-Farber Cancer Institute and Children’s Hospital, Tina N. Davis & Andrew L. Kung * Howard Hughes Medical Institute,, D. Gary Gilliland * Division of

Hematologic Neoplasia, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA, James E. Bradner Authors * Raymond E. Moellering View author publications You

can also search for this author inPubMed Google Scholar * Melanie Cornejo View author publications You can also search for this author inPubMed Google Scholar * Tina N. Davis View author

publications You can also search for this author inPubMed Google Scholar * Cristina Del Bianco View author publications You can also search for this author inPubMed Google Scholar * Jon C.

Aster View author publications You can also search for this author inPubMed Google Scholar * Stephen C. Blacklow View author publications You can also search for this author inPubMed Google

Scholar * Andrew L. Kung View author publications You can also search for this author inPubMed Google Scholar * D. Gary Gilliland View author publications You can also search for this author

inPubMed Google Scholar * Gregory L. Verdine View author publications You can also search for this author inPubMed Google Scholar * James E. Bradner View author publications You can also

search for this author inPubMed Google Scholar CORRESPONDING AUTHORS Correspondence to Gregory L. Verdine or James E. Bradner. ETHICS DECLARATIONS COMPETING INTERESTS [COMPETING INTERESTS:

G.L.V. is a shareholder in and paid consultant of Aileron Therapeutics, which has been granted a license by Harvard University and the Dana Farber Cancer Institute to develop the stapled

peptide technology.] SUPPLEMENTARY INFORMATION SUPPLEMENTARY INFORMATION This file contains Supplementary Figures 1 - 8 with Legends and Supplementary Tables 1 - 2. (PDF 3034 kb) POWERPOINT

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permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Moellering, R., Cornejo, M., Davis, T. _et al._ Direct inhibition of the NOTCH transcription factor complex. _Nature_ 462, 182–188 (2009).

https://doi.org/10.1038/nature08543 Download citation * Received: 29 January 2009 * Accepted: 25 September 2009 * Issue Date: 12 November 2009 * DOI: https://doi.org/10.1038/nature08543

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