A-769662

A-769662は0.8μMのEC50による強力な、可逆的なAMPを起動するプロテインキナーゼ(AMPK)活性剤で、3.2μMでIC50で脂肪酸合成を禁止します。

目録号S2697
5 5 1レビュー 4製品表彰状
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A-769662 化学構造
分子量: 360.39

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製品情報

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製品の説明

生物活性

情報 A-769662は0.8μMのEC50による強力な、可逆的なAMPを起動するプロテインキナーゼ(AMPK)活性剤で、3.2μMでIC50で脂肪酸合成を禁止します。
目標

AMPK

Fatty acid synthesis

IC50

0.8 μM

3.2 μM [1]

In vitro試験 A-769662 stimulates partially purified rat liver AMPK with EC50 with 0.8 μM. A-769662 activates AMPK purified from multiple tissues and species in a dose-responsive manner with modest variations in observed EC50s. EC50s determined for A-769662 using partially purified AMPK extracts from rat heart, rat muscle, or human embryonic kidney cells (HEKs) are 2.2 mM, 1.9 mM, or 1.1 mM, respectively. A 4 hours treatment of primary rat hepatocytes with A-769662 dose-dependently increases ACC phosphorylation, which correlated inhibition of fatty acid synthesis with IC50 of 3.2 μM. A-769662 also inhibits fatty acid sythesis in mouse hepatocytes with IC50 with 3.6 μM [1] A-769662 activates AMPK both allosterically and by inhibiting dephosphorylation of AMPK on Thr-172, similar to the effects of AMP. [2] A-769662 inhibits proteasomal function by an AMPK-independent mechanism. A-769662 affects the in vitro activity of purified 26S proteasomes but not the in vitro activity of purified 20S proteasomes. A-769662 has toxic effects on MEF cells. [3] A recent research shows A-769662 inhibited cell proliferation and DNA synthesis. [4]
In vivo試験 Short-term treatment of normal Sprague Dawley rats with A-769662 decreases liver malonyl CoA levels and the respiratory exchange ratio, VCO2/VO2, indicating an increased rate of whole-body fatty acid oxidation. Treatment of ob/ob mice with 30 mg/kg b.i.d. A-769662 decreases hepatic expression of PEPCK, G6Pase, and FAS, lowers plasma glucose by 40%, reduced body weight gain and significantly decreases both plasma and liver triglyceride levels. [1]
臨床試験
特集

推薦された実験操作 (公開の文献だけ)

キナーゼアッセイ:

[1]

96-well AMPK assay AMPK activity is measured by monitoring phosphorylation of the SAMS peptide substrate (20 mM in standard assays and 100 mM in additivity assays) following a previously described protocol (Anderson et al., 2004). To determine whether A-769662-induced AMPK activation occurs in a reversible manner, AMP or A-769662 are preincubated with rat liver AMPK for 10 minutes at 20 times standard assay concentrations prior to dilution and measurement of AMPK activity.
Fatty Acid Synthesis Assay Primary rat hepatocytes are isolated and plated at 5 × 104 cells per well on BioCoat, collagen-coated, black-walled 96-well plates in DMEM supplemented with 10% FBS, 5 mM glucose, 1 mM sodium pyruvate, 2 mM L-glutamine, 25 mM HEPES, 0.1 m

細胞アッセイ:

[3]

細胞系 MEF cells
濃度 300 μM
処理時間 24 hours
方法

Cell viability of MEF cells treated or not with A-769662 is performed as follows: cells are harvested by trypsinization and incubated with 0.5 mg/mL RNase and 50 μg/mL propidium iodine at room temperature in the dark; cell viability is analyzed by flow cytometry using a FACScanto flow cytometer, using an excitation laser at 488 nm and a propidium iodine fluorescence detection at 600 nm. To determine the proportion of cells in each phase of the cell cycle, cells are harvested by trypsinization, collected by centrifugation, washed in PBS and fixed overnight in 80% ethanol at -20 °C. Subsequently, these fixed cells are centrifuged to remove the fixative and incubated for 20 minutes in the dark at room temperature in PBS containing 0.5 mg/mL RNase and 50 μg/mL propidium iodine. Flow cytometry analysis is performed as above. The proportion of cells in G1, S, and G2 is determined using the MODFIT program. Cell culture pictures are taken at the indicated times using a camera coupled to an inverted microscope with a 20 × objective.

動物実験:

[1]

動物モデル Sprague Dawley rats
製剤 A-769662 is dissolved in DMSO.
投薬量 30 mg/kg
管理 Administered via i.p.
Solubility 1% DMSO/30% polyethylene glycol/1% Tween 80 30 mg/mL
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesBaboonDogMonkeyRabbitGuinea pigRatHamsterMouse
Weight (kg)121031.80.40.150.080.02
Body Surface Area (m2)0.60.50.240.150.050.0250.020.007
Km factor202012128653
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

参考

化学情報

Download A-769662 SDF
分子量 360.39
化学式

C20H12N2O3S

CAS No. 844499-71-4
保管 2年-20℃
6月-80℃in DMSO
別名
溶解度 (25°C) * In vitro DMSO 72 mg/mL (199 mM)
<1 mg/mL (<1 mM)
エタノール <1 mg/mL (<1 mM)
In vivo 1% DMSO/30% polyethylene glycol/1% Tween 80 30 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
化学名 Thieno[2,3-b]pyridine-5-carbonitrile, 6,7-dihydro-4-hydroxy-3-(2'-hydroxy[1,1'-biphenyl]-4-yl)-6-oxo-

研究分野

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Source , , Cancer Res, 2014, 74(1):298-308. A-769662 purchased from Selleck
Method MTT
Cell Lines H1299, A549
Concentrations 100 nM
Incubation Time 48 h
Results A SIRT1 inhibitor (EX527) induced drug resistances under normoxia, which was reversed by an AMPK activator (A769662).

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