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Beschreibung

A cell-permeable benzoylthiourea compound that acts as a reversible inhibitor of class III HDAC sirtuins (IC50 against SirT2 ~10 µ,M). Based on studies using the more soluble analog Tenovin-6, Tenovin-1 is expected not to compete with substrate binding and display lower potency against SirT1/3 (IC50 = 21/67 µ,M using Tenovin-6). Tenovin-1 (10 µ,M) up-regulates cellular p53 protein, but not mRNA, level in MCF-7 (>=6-fold in 6 h), presumably by blocking mdm2-mediated p53 degradation. Two day Tenovin-1 treatment (10 µ,M) results in selective killing of cancer cells with functional p53, but not p53-lacking cancer cells or normal human dermal fibroblasts. Despite its low aqueous solubility, administration of Tenovin-1 suspension is shown to effectively reduce BL2 and ARN8 xenographs in mice in vivo (>=50% reduction with 92 mg/kg daily i.p.)., A cell-permeable benzoylthiourea compound that acts as a reversible inhibitor of class III HDAC sirtuins against SirT2 (IC50 = ~ 10 µ,M). Based on studies using the more soluble analog Tenovin-6, Tenovin-1 is expected not to compete with substrate binding and display lower potency against SirT1/3 (IC50 = 21/67 µ,M using Tenovin-6). Tenovin-1 (10 µ,M) up-regulates cellular p53 protein, but not mRNA, level in MCF-7 (>=6-fold in 6 h), presumably by blocking mdm2-mediated p53 degradation. Two day Tenovin-1 treatment (10 µ,M) results in selective killing of cancer cells with functional p53, but not p53-lacking cancer cells or normal human dermal fibroblasts. Despite its low aqueous solubility, administration of Tenovin-1 suspension is shown to effectively reduce BL2 and ARN8 xenographs in mice in vivo (>=50% reduction with 92 mg/kg, daily, i.p.).