人们对NOTCH复合物有极大兴趣，这是由于它作为基因转录的一个主要发育调控因子、γ-分泌酶的一个基质和在包括T-细胞白血病在内的很多癌症中被不适当激发的一个致癌基因等等所起的作用。同大多数转录因子一样，NOTCH过去也被认为是不能用可透过细胞的合成分子来定位的。但是现在，一个很有希望的NOTCH拮抗分子已被设计出来，并被发现在一个小鼠模型中能够有效抑制白血病的发展。
由烃类组成的肽SAHM1通过阻止活性转录复合物的形成来发挥作用，为研究NOTCH的作用提供一个有潜在价值的工具，同时也为治疗药物提供一个起点。另外，转录激活复合物的直接定位也许还适用于以前被认为不可定位的几个其他转录因子复合物。（生物谷Bioon.com）
生物谷推荐原始出处：
Nature 462, 182-188 (12 November 2009) | doi:10.1038/nature08543
Direct inhibition of the NOTCH transcription factor complex
Raymond E. Moellering1,2,3, Melanie Cornejo4, Tina N. Davis6, Cristina Del Bianco5, Jon C. Aster5, Stephen C. Blacklow5, Andrew L. Kung6, D. Gary Gilliland4,7, Gregory L. Verdine1,3 & James E. Bradner2,3,8
1 Department of Chemistry & Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA
2 Chemical Biology Program, Broad Institute of Harvard & MIT, Cambridge, Massachusetts 02142, USA
3 Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA
4 Division of Hematology, Brigham & Women's Hospital,
5 Department of Pathology, Brigham & Women's Hospital,
6 Department of Pediatric Oncology, Dana-Farber Cancer Institute and Children's Hospital,
7 Howard Hughes Medical Institute,
8 Division of Hematologic Neoplasia, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
9 Correspondence to: Gregory L. Verdine1,3James E. Bradner2,3,8 Correspondence and requests for materials should be addressed to J.E.B. or G.L.V.
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 -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.
