西亚试剂：Direct inhibition of the NOTCH transcription factor complex

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.

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