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Beschreibung

A cell-permeable, stabilized hydrocarbon-stapled alpha-helical peptide that targets a critical protein-protein interface and prevents assembly in the NOTCH1 trans-activation complex. Soluble FITC-SAHM1 was found to bind the pre-formed RAMANK-CSL complex (Kd = 0.12 µ,M) competitively with MAML1, whereas the unmodified FITC-MAML1 (21-36) peptide bound the complex with markedly diminished affinity in an in vitro pull down assay. Treatment of KOPT-K1 cell lines with 20 µ,M of compound results in the suppression of NOTCH1 target genes, HES4, DTX1, and HES1. A consistent repressive effect on NOTCH1-activated gene expression by this compound was observed across a panel of human T-ALL cell lines, containing diverse mutant NOTCH1 alleles. In HeLa cells, this peptide also inhibited the expression of ICN1 (IC50 = 6.56 µ,M) dose-dependently in a luciferase reporter-gene assay, as well as that of beta-lactamase (IC50<2.5 µ,M) in a second reporter-gene assay. Furthermore, treatment with this peptide inhibits NOTCH-mediated proliferation in cultured cells at 15 µ,M, and in a mouse model of T-ALL cells at 30 mg/kg twice daily.