AT-406 纯度:98.80% 2mg

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AT-406 纯度:98.80% 2mg

市场价：: 670.00

促销价：: ¥670.00

货号：HY-15454

品牌：MCE

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北京朝阳

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商品介绍
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AT-406 是一种有效的，可口服的 Smac 模拟物，为 IAPs 的拮抗剂，能够抑制 XIAP，cIAP1 和 cIAP2 蛋白，K_i 值分别为 66.4，1.9 和 5.1 nM。

Description

AT-406 is a potent and orally bioavailable Smac mimetic and an antagonist of IAPs, and it binds to XIAP, cIAP1, and cIAP2 proteins with K_i of 66.4, 1.9, and 5.1 nM, respectively.

IC₅₀ & Target

Ki: 66.4 nM (XIAP), 1.9 nM (cIAP1), 5.1 nM (cIAP2)

In Vitro

AT-406 mimic closely the AVPI peptide in both hydrogen bonding and hydrophobic interactions with XIAP, with additional hydrophobic contacts with W323 of XIAP. AT-406 is more sensitive to these IAPs than Smac AVPI peptide with 50-100 fold binding affinities. AT-406 (1 μM) completely restores the activity of caspase-9, which is suppressed by 500 nM XIAP BIR3 in a cell-free system. In MDA-MB-231 cell, AT-406 induces rapid cellular cIAP1 degradation and also pulls down the cellular XIAP protein. AT-406 effectively inhibits lots of human cancer cell lines and shows IC₅₀ of 144 and 142 nM in MDA-MB-231 cell and SK-OV-3 ovarian cell, with low toxicity against normal-like human breast epithelial MCF-12F cells and primary human normal prostate epithelial cells. AT-406 induces apoptosis in MDA-MB-231 cell by inducing activation of caspase-3 and cleavage of PARP^[1]. AT-406 displays single agent activity in ovarian cancer cell lines. The IC₅₀ values of AT-406 in these ovarian cancer cells range from 0.05-0.5 µg/mL. AT-406 exhibits anti-ovarian cancer efficacy both as a single agent and in combination with carboplatin. AT-406 (30 μg/mL) induced degradation of XIAP in the drug sensitive ovarian cancer cell lines^[2].

In Vivo

AT-406 has good pharmacokinetic properties and oral bioavailability in mice, rats, non-human primates, and dogs. In the MDA-MB-231 xenograft, AT-406 effectively induces cIAP1 degradation and processing of procaspase-8, cleavage of PARP in tumor tissues at 100 mg/kg with well toleration even at 200 mg/kg. AT-406 induces significant tumor growth inhibition with p of 0.0012 at 100 mg/kg^[2]. SM-406 (30, 100 mg/kg, p.o.) decreases the plasma and tumor in tumor-bearing mice^[3].

Solvent & Solubility

In Vitro:

10 mM in DMSO

Preparing
Stock Solutions

Concentration Solvent Mass	1 mg	5 mg	10 mg

1 mM	1.7803 mL	8.9014 mL	17.8028 mL
5 mM	0.3561 mL	1.7803 mL	3.5606 mL
10 mM	0.1780 mL	0.8901 mL	1.7803 mL

* Please refer to the solubility information to select the appropriate solvent.

References

[1]. Cai Q, et al. A potent and orally active antagonist (SM-406/AT-406) of multiple inhibitor of apoptosis proteins (IAPs) in clinical development for cancer treatment. J Med Chem. 2011 Apr 28;54(8):2714-26.

[2]. Brunckhorst MK, et al. AT-406, an orally active antagonist of multiple inhibitor of apoptosis proteins, inhibits progression of human ovarian cancer. Cancer Biol Ther. 2012 Jul;13(9):804-11.

[3]. Zhang T, et al. Physiologically based pharmacokinetic and pharmacodynamic modeling of an antagonist (SM-406/AT-406) of multiple inhibitor of apoptosis proteins (IAPs) in a mouse xenograft model of human breast cancer. Biopharm Drug Dispos. 2013 Sep;34(6):

Kinase Assay ^[1]	MDA-MB-231 cell lysates are prepared by solubilizing cells in ice cold buffer containing KCl (50 mM), EGTA (5 mM), MgCl₂ (2 mM) DTT (1 mM), 0.2% CHAPS and HEPES, (50 mM, pH 7.5), containing cocktail protease inhibitors, incubating on ice for 10 minutes, then freezing in liquid nitrogen. Cytochrome c and dATP are added to the cell lysates, which are then incubated at 30°C in a water bath for 60 minutes to activate caspase-9. Addition of recombinant XIAP BIR3 protein dose-dependently suppresses the activity of caspase-9. Different concentrations of a tested Smac mimetic (1 nM-100 μM) are added to determine the restoration of the activity of these caspases. MCE has not independently confirmed the accuracy of these methods. They are for reference only.
Cell Assay ^[1]	Cells are seeded in 96-well flat bottom cell culture plates at a density of 3-4 ×10³ cells/well with AT-406 and incubated for 4 days. The rate of cell growth inhibition after treatment with different concentrations of AT-406 is determined by assaying with (2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium monosodium salt (WST-8). WST-8 is added to each well to a final concentration of 10%, and then the plates are incubated at 37°C for 2−3 hours. The absorbance of the samples is measured at 450 nm using a TECAN ULTRA reader. Concentration of AT-406 that inhibits cell growth by 50% (IC₅₀) is calculated by comparing absorbance in the untreated cells and the cells treated with AT-406. MCE has not independently confirmed the accuracy of these methods. They are for reference only.
Animal Administration ^[1]	SCID mice (8-10 per group) bearing MDA-MB-231 xenograft tumors are treated with different doses of compound 2, or 7.5 mg/kg of Taxotere or vehicle control daily, 5 days a week for 2 weeks. Tumor sizes and animal weights are measured 3 times a week during the treatment and twice a week after the treatment. Data are presented as mean tumor volumes±SEM. Statistical analyses are performed by two-way ANOVA and unpaired two-tailed t test, using Prism. P < 0.05 is considered statistically significant. MCE has not independently confirmed the accuracy of these methods. They are for reference only.
References	[1]. Cai Q, et al. A potent and orally active antagonist (SM-406/AT-406) of multiple inhibitor of apoptosis proteins (IAPs) in clinical development for cancer treatment. J Med Chem. 2011 Apr 28;54(8):2714-26. [2]. Brunckhorst MK, et al. AT-406, an orally active antagonist of multiple inhibitor of apoptosis proteins, inhibits progression of human ovarian cancer. Cancer Biol Ther. 2012 Jul;13(9):804-11. [3]. Zhang T, et al. Physiologically based pharmacokinetic and pharmacodynamic modeling of an antagonist (SM-406/AT-406) of multiple inhibitor of apoptosis proteins (IAPs) in a mouse xenograft model of human breast cancer. Biopharm Drug Dispos. 2013 Sep;34(6):