Direct inhibition of the NOTCH transcription factor complex

Article

关键词: ACUTE LYMPHOBLASTIC-LEUKEMIA;    GAMMA-SECRETASE INHIBITORS;    T-CELL LEUKEMIA;    PROGENITOR CELLS;    HUMAN HOMOLOG;    C-MYC;    MUTATIONS;    GENE;    MASTERMIND;    ACTIVATION;   

DOI  :  10.1038/nature08543

来源: SCIE

【 摘 要 】

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.

【 授权许可】

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