Direct inhibition of the NOTCH transcription factor complex

被引：626

作者：

Moellering, Raymond E. ^{[1
,2
,3
]}

Cornejo, Melanie ^{[4
]}

Davis, Tina N. ^{[6
,7
]}

Del Bianco, Cristina ^{[5
]}

Aster, Jon C. ^{[5
]}

Blacklow, Stephen C. ^{[5
]}

Kung, Andrew L. ^{[6
,7
]}

Gilliland, D. Gary ^{[4
,8
]}

Verdine, Gregory L. ^{[2
,3
]}

Bradner, James E. ^{[1
,3
,9
]}

机构：

[1] Broad Inst Harvard & MIT, Chem Biol Program, Cambridge, MA 02142 USA

[2] Harvard Univ, Dept Chem & Biol Chem, Cambridge, MA 02138 USA

[3] Dana Farber Canc Inst, Program Canc Chem Biol, Boston, MA 02115 USA

[4] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Hematol, Boston, MA 02115 USA

[5] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA

[6] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA

[7] Harvard Univ, Sch Med, Childrens Hosp, Boston, MA 02115 USA

[8] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA

[9] Harvard Univ, Sch Med, Dana Farber Canc Inst, Div Hematol Neoplasia, Boston, MA 02115 USA

来源：

NATURE | 2009年 / 462卷 / 7270期

基金：

美国国家卫生研究院;

关键词：

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

D O I：

10.1038/nature08543

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

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.

引用

页码：182 / U57

页数：9

共 50 条

[1] Notch signaling: Cell fate control and signal integration in development [J].