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

Correspondence to: Gregory L. Verdine^1,3James E. Bradner^2,3,8 Correspondence and requests for materials should be addressed to J.E.B. (Email: james_bradner@dfci.harvard.edu) or G.L.V. (Email: gregory_verdine@harvard.edu).

Abstract

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.

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

Correspondence to: Gregory L. Verdine^1,3James E. Bradner^2,3,8 Correspondence and requests for materials should be addressed to J.E.B. (Email: james_bradner@dfci.harvard.edu) or G.L.V. (Email: gregory_verdine@harvard.edu).