Direct inhibition of the NOTCH transcription factor complex.
Direct inhibition of the NOTCH transcription factor complex.
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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.
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影响因子：
30.8
作者：
Li, LH;Krantz, ID;Spinner, NB
通讯作者：
Spinner, NB
影响因子：
64.5
作者：
Nam, Y;Sliz, P;Blacklow, SC
通讯作者：
Blacklow, SC
影响因子：
6
作者：
Becker, Christian M.;Wright, Renee D.;D'Amato, Robert J.
通讯作者：
D'Amato, Robert J.
影响因子：
64.8
作者：
Garg, V;Muth, AN;Srivastava, D
通讯作者：
Srivastava, D
影响因子：
2.9
作者：
CHEN, YH;YANG, JT;CHAU, KH
通讯作者：
CHAU, KH