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Direct inhibition of the NOTCH transcription factor complex

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  • Raymond E. Moellering

    (Harvard University, Cambridge, Massachusetts 02138, USA
    Chemical Biology Program, Broad Institute of Harvard & MIT, Cambridge, Massachusetts 02142, USA
    Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA)

  • Melanie Cornejo

    (Brigham & Women’s Hospital)

  • Tina N. Davis

    (Dana-Farber Cancer Institute and Children’s Hospital)

  • Cristina Del Bianco

    (Brigham & Women’s Hospital)

  • Jon C. Aster

    (Brigham & Women’s Hospital)

  • Stephen C. Blacklow

    (Brigham & Women’s Hospital)

  • Andrew L. Kung

    (Dana-Farber Cancer Institute and Children’s Hospital)

  • D. Gary Gilliland

    (Brigham & Women’s Hospital
    Howard Hughes Medical Institute,)

  • Gregory L. Verdine

    (Harvard University, Cambridge, Massachusetts 02138, USA
    Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA)

  • James E. Bradner

    (Chemical Biology Program, Broad Institute of Harvard & MIT, Cambridge, Massachusetts 02142, USA
    Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA
    Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA)

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 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.

Suggested Citation

  • Raymond E. Moellering & Melanie Cornejo & Tina N. Davis & Cristina Del Bianco & Jon C. Aster & Stephen C. Blacklow & Andrew L. Kung & D. Gary Gilliland & Gregory L. Verdine & James E. Bradner, 2009. "Direct inhibition of the NOTCH transcription factor complex," Nature, Nature, vol. 462(7270), pages 182-188, November.
    • Handle: RePEc:nat:nature:v:462:y:2009:i:7270:d:10.1038_nature08543
    DOI: 10.1038/nature08543
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    Citations

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    Cited by:

    1. Nikolai Schleussner & Pierre Cauchy & Vedran Franke & Maciej Giefing & Oriol Fornes & Naveen Vankadari & Salam A. Assi & Mariantonia Costanza & Marc A. Weniger & Altuna Akalin & Ioannis Anagnostopoulo, 2023. "Transcriptional reprogramming by mutated IRF4 in lymphoma," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    2. Olena S. Tokareva & Kunhua Li & Tara L. Travaline & Ty M. Thomson & Jean-Marie Swiecicki & Mahmoud Moussa & Jessica D. Ramirez & Sean Litchman & Gregory L. Verdine & John H. McGee, 2023. "Recognition and reprogramming of E3 ubiquitin ligase surfaces by α-helical peptides," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    3. Yuri Frosi & Yen-Chu Lin & Jiang Shimin & Siti Radhiah Ramlan & Kelly Hew & Alf Henrik Engman & Anil Pillai & Kit Yeung & Yue Xiang Cheng & Tobias Cornvik & Par Nordlund & Megan Goh & Dilraj Lama & Za, 2022. "Engineering an autonomous VH domain to modulate intracellular pathways and to interrogate the eIF4F complex," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    4. Wenxue Ma & Alejandro Gutierrez & Daniel J Goff & Ifat Geron & Anil Sadarangani & Christina A M Jamieson & Angela C Court & Alice Y Shih & Qingfei Jiang & Christina C Wu & Kang Li & Kristen M Smith & , 2012. "NOTCH1 Signaling Promotes Human T-Cell Acute Lymphoblastic Leukemia Initiating Cell Regeneration in Supportive Niches," PLOS ONE, Public Library of Science, vol. 7(6), pages 1-14, June.

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