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A-674563

产品号 S2670 公司名称 Selleck Chemicals
CAS号 552325-73-2 公司网站 http://www.selleckchem.com
分子式 C22H22N4O 电 话 (877) 796-6397
分子量 358.43628 传 真 (832) 582-8590
纯 度 电子邮件 sales@selleckchem.com
保 存 -20°C Chembase数据库ID: 6176

产品价格信息

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产品别名

标题
A-674563
IUPAC标准名
5-{5-[(2S)-2-amino-3-phenylpropoxy]pyridin-3-yl}-3-methyl-1H-indazole
IUPAC传统名
5-{5-[(2S)-2-amino-3-phenylpropoxy]pyridin-3-yl}-3-methyl-1H-indazole

产品登记号

CAS号 552325-73-2

产品性质

作用靶点 Akt
成盐信息 Free Base
保存条件 -20°C

产品详细信息

详细说明 (English)
Biological Activity
Description A-674563 shows Akt1 inhibitory effect with Ki of 11 nM.
Targets Akt1 PKA CDK2
IC50 11 nM (Ki) 16 nM (Ki) 46 nM (Ki) [1]
In Vitro A-674563 is achieved from A-443654 by replacing the indole with a phenyl moiety and getting oral activity. A-674563 slows proliferation of tumor cells with EC50 of 0.4 μM. [1] A-674563 does not inhibit Akt phosphorylation per se, but blocks the phosphorylation of Akt downstream targets in a dose-dependent manner. A-674563 induced Akt blockade results in decreased STS cell downstream target phosphorylation and tumor cell growth inhibiton. A-674563 induces G2 cell cycle arrest and apoptosis in STS cells. [2]
In Vivo 20 mg/kg A-674563 increases plasma insulin in an oral glucose tolerance test. A-674563 shows no significant monotherapy tumor inhibitory activity; the efficacy of the combination therapy is significantly improved compared to paclitaxel monotherapy. [1] A674563-treated (20 mg/kg/bid, p.o.) mice exhibits slower tumor growth and more than 50% decrease in the tumor volume at the termination of the study compared with that in control group. [2] A-674563 is identified to have drastically improved PK profile with oral bioavailability of 67% in mouse, but is 70-fold less active than A-443654. [3]
Clinical Trials
Features
Combination Therapy
Description A-674563 increases the efficacy of Paclitaxel in a PC-3 xenograft model. [1]
Protocol
Kinase Assay [1]
Akt Kinase Assay The kinase assay uses His-Akt1 and a biotinylated mouse Bad peptide as substrate. The kinase assay is carried out at room temperature for 30 minutes in 50 μL of reaction buffer [20 mM HEPES, pH 7.5, 10 mM MgCl2, 0.1% (w/v) Triton X-100, 5 μM ATP (Km = 40 μM), 5 μM peptide (Km = 15 μM), 1 mM DTT, 60 ng of Akt1, and 0.5 μCi of [γ-33P]ATP] in the presence of different concentrations of A-674563. Each reaction is stopped by adding 50 μL of termination buffer (0.1 M EDTA, pH 8.0, and 4 M NaCl). The biotinylated Bad peptides are immobilized on streptavidin-coated FLASH plates. Afterbeing washed with PBS-Tween 20 (0.05%), the 33P phosphopeptide captured on the FLASH plates is measured with a TopCount Packard Instruments γ counter.
Cell Assay [1]
Cell Lines MiaPaCa-2 cells
Concentrations 0-30 μM
Incubation Time 48 hours
Methods The cells on 96-well plates are gently washed with 200 μL of PBS. Alamar Blue reagent is diluted 1:10 in normal growth media. The diluted Alamar Blue reagent (100 M) is added to each well on the 96-well plates and incubated until the reaction is complete as per manufacturer’s instructions. Analysis is done using an fmax Fluorescence Microplate Reader, set at the excitation wavelength of 544 nm and emission wavelength of 595 nm. Data are analyzed using SOFTmax PRO software provided by the manufacturer.
Animal Study [1]
Animal Models Fasted mice
Formulation Dissolved in DMSO.
Doses 20 or 100 mg/kg
Administration A-674563 is administered 30 minutes before the 1 g/kg glucose challenge.
References
[1] Luo Y, et al, Mol Cancer Ther, 2005, 4(6), 977-986.
[2] Zhu QS, et al, Cancer Res, 2008, 68(8), 2895-2903.
[3] Tatsuya Okuzumi, et al, Mol Biosyst, 2010, 6(8), 1389-1402.