人們對NOTCH復合物有極大興趣,，這是由于它作為基因轉(zhuǎn)錄的一個主要發(fā)育調(diào)控因子、γ-分泌酶的一個基質(zhì)和在包括T-細胞白血病在內(nèi)的很多癌癥中被不適當激發(fā)的一個致癌基因等等所起的作用,。同大多數(shù)轉(zhuǎn)錄因子一樣,，NOTCH過去也被認為是不能用可透過細胞的合成分子來定位的。但是現(xiàn)在，一個很有希望的NOTCH拮抗分子已被設(shè)計出來,，并被發(fā)現(xiàn)在一個小鼠模型中能夠有效抑制白血病的發(fā)展,。
由烴類組成的肽SAHM1通過阻止活性轉(zhuǎn)錄復合物的形成來發(fā)揮作用，為研究NOTCH的作用提供一個有潛在價值的工具,，同時也為治療藥物提供一個起點,。另外，轉(zhuǎn)錄激活復合物的直接定位也許還適用于以前被認為不可定位的幾個其他轉(zhuǎn)錄因子復合物,。（生物谷Bioon.com）
生物谷推薦原始出處：
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.
