SRT1720 HCl

Orally

Human vascular endothelial cells (HUVECs)

5 uM

200 mg/kg

0.16 uM (EC1.5) [1], 0.16 uM (EC1.5) [1], 0.16 uM (EC1.5) [1], 0.16 uM (EC1.5) [1], 0.16 uM (EC1.5) [1], 0.16 uM (EC1.5) [1]

In DIO mice SRT1720 mimics several of the effects observed after calorie restriction including improved insulin sensitivity, normalized glucose and insulin levels, and increased mitochondrial capacity. In addition, in diet-induced obese and genetically obese mice, SRT1720 improves insulin sensitivity, lower plasma glucose, and increase mitochondrial capacity. Thus, SRT1720 is a promising new therapeutic agent for treating diseases of ageing such as type 2 diabetes. Consistent with improved glucose tolerance, the glucose infusion rate required to maintain euglycaemia is approximately 35% higher in SRT1720-treated fa/fa rats, and the total glucose disposal rate is increased by approximately 20%. [1] SRT1720 also prevents multiple myeloma tumor growth. SRT1720 increases the cytotoxic activity of bortezomib or dexamethasone. [2]

SIRT1 fluorescence polarization assay, In the SIRT1 FP assay, SIRT1 activity is monitored using a 20 amino acid peptide (Ac-Glu-Glu-Lys(biotin)-Gly-Gln-Ser-Thr-Ser-Ser-His-Ser-Lys(Ac)-Nle-Ser-Thr-Glu-Gly–Lys(MR121 or Tamra)-Glu-Glu-NH2) derived from the sequence of p53. The peptide is N-terminally linked to biotin and C-terminally modified with a fluorescent tag. The reaction for monitoring enzyme activity is a coupled enzyme assay where the first reaction is the deacetylation reaction catalyzed by SIRT1 and the second reaction is cleavage by trypsin at the newly exposed lysine residue. The reaction is stopped and streptavidin is added in order to accentuate the mass differences between substrate and product. The sensitivity of the FP assay allows identification of SRT1720. The fluorescence polarization reaction conditions are as follows: 0.5 uM peptide substrate, 150 uM betaNAD+, 0-10 nM SIRT1, 25 mM Tris-acetate pH 8, 137 mM Na-Ac, 2.7 mM K-Ac, 1 mM Mg-Ac, 0.05% Tween-20, 0.1% Pluronic F127, 10 mM CaCl 5 mM DTT, 0.025% BSA, and 0.15 mM nicotinamide. The reaction is incubated at 37 C and stopped by addition of nicotinamide, and trypsin is added to cleave the deacetylated substrate. This reaction is incubated at 37 C in the presence of 1 uM streptavidin. Fluorescent polarization is determined at excitation (650 nm) and emission (680 nm) wavelengths.

506, 02

DMSO 38 mg/mL, Water <1 mg/mL, Ethanol <1 mg/mL