Direct inhibition of the NOTCH transcription factor complex
Direct inhibition of the NOTCH transcription factor complex
复制标题
DOI：
10.1038/nature08660
复制
发表时间：
2010
期刊：
影响因子：
64.8
通讯作者：
R. Moellering;Melanie Cornejo;Tina N. Davis;Cristina Del Bianco;Jon C. Aster;S. Blacklow;Andrew L. Kung-Andre
中科院分区：
文献类型：
--
作者：
R. Moellering;Melanie Cornejo;Tina N. Davis;Cristina Del Bianco;Jon C. Aster;S. Blacklow;Andrew L. Kung-Andre
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.
