生物活性

Tenovin-1, areversible inhibitor of class III HDACs (SIRT1 and SIRT2), affects a variety ofcancer cell lines in a p53-dependent manner. Tenovin-1 is a compound that belongs to the class of Tenovins, and inhibits SIRT1 and SIRT2. SIRT1 and SIRT2 are protein-deacetylases and are members of the NAD+-dependent class III histone deacetylases. Tenovin-1 has been shown to activate and elevate acetylated p53 levels, induce apoptosis in vitro, and acetylate histone H4. P53 activator that protects against MDM2-mediated p53 degradation. Elevates levels of p53 and p21CIP/WAF1 and induces expression from an endogenous p53-dependent promoter. Exhibits potent antiproliferative activity in vitro.

Sirtuinsactivities of tenovin-1[1][2]

体外研究

体内研究

激酶实验

SIRT activity[3]

SIRT enzyme activity was measured usingSIRT-Glow assay and screening system. This assay is a single reagent- addition,homogeneous, luminescent assay that measures the relative activity of the(NAD+)-dependent HDAC class III SIRTs. For assay, 20 × 10³ cells/well were plated in 25μl medium with or without tenovin-1 and incubated for24 h. Subsequently 25μl of assay reagent was added to each well, and the plateswere incubated at room temperature for 15 min, in dark, followed by luminescentsignal measurement. Data were represented as percent reduction in SIRTactivity, normalized to no treatment control.

细胞实验

Cell culture[4]

U251, SNB-75 cell lines were cultured inRPMI medium supplemented with 10% FBS and 1% penicillin/streptomycin. Thecultured cells were incubated at 37 ℃ in a humidified 5% CO₂ incubator.

Nuclearsize measurement

The cells were seeded onto an 8-wellculture slide and treated with drugs as indicated. The cells were fixed with 4%formaldehyde solution and then permeabilized with 0.5% Triton X-100 solution.The cells were then stained with 50ng/mL DAPI and visualized using an AxioObserver.Z1 fluorescence microscope. Nuclear size was measured using ImageJsoftware.

动物实验

Tumor Xenograft Studies[1]

Female SCID mice were injectedsubcutaneously with 1x10⁶ ARN8 cells suspended in matrigel. Tumorswere allowed to reach a size of approximately 10 mm³. Tenovin-1 (in70% cyclodextrin) was administered daily (14 days) by intraperitoneal injectionat 92.5 mg/kg and tumor growth was measured over a period of 18 days. Note thatmice were left untreated from day 15 to day 18. Control animals were treatedwith 70% cyclodextrin. Tumor diameters were measured using calipers, andvolumes were calculated using the equation V = p4/3[(d1 + d2)/4]3. Medianvalues of tumor size were calculated for each time point as well as the corresponding95% confidence intervals. Mice receiving tenovin-1 had significantly reducedtumor growth as analysed by appropriate choice of 2-sample t-test (normaldistributions) and Mann Whitney U-test (non-normal distributions). 

不同实验动物依据体表面积的等效剂量转换表（数据来源于FDA指南）

例如，已知某工具药用于小鼠的剂量为88 mg/kg , 则用于大鼠的剂量换算方法：将88 mg/kg 乘以小鼠的Km系数（3），再除以大鼠的Km系数（6），得到该药物用于大鼠的等效剂量44 mg/kg。

参考文献

[1] Lain S, Hollick JJ, Campbell J, et al. Discovery, in vivo activity, and mechanism of action of a small-molecule p53 activator. Cancer Cell. 2008;13(5):454-463.
[2] Wilking MJ, Singh CK, Nihal M, Ndiaye MA, Ahmad N. Sirtuin deacetylases: a new target for melanoma management. Cell Cycle. 2014;13(18):2821-2826.
[more]

体内溶解度
约20 mg/mL

Clinical Trial Information ( data from http://clinicaltrials.gov )

注：以上所有数据均来自公开文献，并不保证对所有实验均有效，数据仅供参考。

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