A-769662 化学構造
分子量: 360.39

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製品説明

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製品の説明

生物活性

製品説明 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。
ターゲット

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]
Cell Data
Cell LinesAssay TypeConcentrationIncubation TimeFormulationActivity DescriptionPMID
mouse hepatocytes MmfkSpVv[3Srb36gZZN{[Xl? M1rsfFEhdU1? NXzsb5NqTE2VTx?= MX\pcohq[mm2czDmZZR1gSCjY3nkJJN6dnSqZYPpd{B4cXSqIFnDOVAhd2ZiMz62JO69VQ>? M1PxNFE3PzV|NUe2
rat hepatocytes NHPNVppHfW6ldHnvckBie3OjeR?= Moj2NUBuVQ>? MVPEUXNQ MorTbY5pcWKrdIOg[oF1fHliYXPp[EB{gW62aHXzbZMhf2m2aDDJR|UxKG:oIEOuOkDPxE1? MWWxOlc2OzV5Nh?=
HEK293 MoPnT4lv[XOnIHHzd4F6 NVLmUZBbOjByIN88US=> MXjEUXNQ NV\GfoF7[WO2aY\heIV{KGWwZH;n[Y5wfXNiQV3QTy=> NYPqNVhCOTd5MkiyOFE>
CCL13 MnvWT4lv[XOnIHHzd4F6 NEPzPXIzODBizszN MVzEUXNQ MofnZYN1cX[jdHXzJIVv\G:pZX7veZMhSU2SSx?= NEDMfY4yPzd{OEK0NS=>
MEFs M3jIU2Z2dmO2aX;uJIF{e2G7 M1jZUVMxOCEQvF2= NFrmemNFVVOR M1zHVolvcGmkaYTzJJBzd3SnYYPvcYFtKG[3bnP0bY9vKGK7IHHuJGFOWEtvaX7k[ZBmdmSnboSgcYVkcGGwaYPt NF;MSpoyQDV7M{W4OC=>
epididymal clear cells NIXBfodHfW6ldHnvckBie3OjeR?= Mkf0NlAxKM7:TR?= M2ruOmROW09? MYXpcohq[mm2czD0bIUheEhvbXXkbYF1\WRiVj3BWHBie2ViYXPjeY12dGG2aX;uJIF1KHSqZTDhdIlk[WxibXXtZpJidmV? MofwNVkzOTF7MUi=
3T3-L1 M{fwe2Z2dmO2aX;uJIF{e2G7 NETnXW4yNjJibV2= M2WyeWROW09? M{j2UIlvcGmkaYTzJFNVOy2OMTDB[Ilxd2enbnXzbZM> NHPZN|kyQTR6M{OwOC=>
3T3-L1 MlrnSpVv[3Srb36gZZN{[Xl? Mm\ZNU4zKG2P NIPU[WhFVVOR NELN[GJqdmirYnn0d{B1cGViRYjwdoV{e2mxbjDv[kBC\Gmyb3flcoV{cXOUZXzheIVlKFS{YX7zZ5JqeHSrb36gSoFkfG:{czDhcoQhVWG{a3Xydy=> M{jM[VE6PDh|M{C0
3T3-L1 NUKyOWR2TnWwY4Tpc44h[XO|YYm= NFvsTVcyNjJibV2= M2C2W2ROW09? MUDpcohq[mm2czDNbZRwfGmlIFPsc45idCCHeIDhcpNqd25? NUDT[lBTOTl2OEOzNFQ>
3T3-L1 NEH4NmdkgXSxdH;4bYNqfHliYYPzZZk> MVSxMlIhdU1? NXPVWZVlTE2VTx?= NVe2eGFE\GWlcnXhd4V{KEOnbHygWoli[mmuaYT5 M1rZdlE6PDh|M{C0
3T3-L1 MWrLbY5ie2ViYYPzZZk> M4rRS|EvOiCvTR?= M4LkcmROW09? MlnrZYN1cX[jdHXzJGFOWEt? MUKxPVQ5OzNyNB?=
L6 skeletal muscle cells M3XseWZ2dmO2aX;uJIF{e2G7 NIe0NVczPTBizszN NYnjbW5GTE2VTx?= MUHhZ5RqfmG2ZYOgRW1RUyC|aXfuZYxqdmdicHH0bJdigXN? NEnUfnMyQTh{OEizOi=>
L6 skeletal muscle cells M2HCVGZ2dmO2aX;uJIF{e2G7 MmPXNlUxKM7:TR?= M3XMSGROW09? NUT1Nm5FcW6qaXLpeJMhfGinIF7hL{1MMy2DVGDhd4UhfHKjboPwc5J1KGGldHn2bZR6KGGwZDDj[YxtKHO3cn\hZ4Uh[WK3bnThcoNm NGTFVGQyQTh{OEizOi=>
MDA-MB231 MnfYRZBweHSxc3nzJIF{e2G7 MmWzOFAxKM7:TR?= MmjPSG1UVw>? NWn1TIJNe2Wwc3n0bZpmeyCqdX3hckBjemWjc4SgZ4Fv[2W{IHPlcIwhdGmwZYOgeI8hXFKDSVytbY5lfWOnZDDhdI9xfG:|aYO= NEDmTYgyQTh7NkS2PS=>
BT474 NUno[HYzSXCxcITvd4l{KGG|c3H5 MnfpOFAxKM7:TR?= MXHEUXNQ NVi5bZhQe2Wwc3n0bZpmeyCqdX3hckBjemWjc4SgZ4Fv[2W{IHPlcIwhdGmwZYOgeI8hXFKDSVytbY5lfWOnZDDhdI9xfG:|aYO= NX\mc4NJOTl6OU[0Olk>
MCF7 NWXtTZpJSXCxcITvd4l{KGG|c3H5 NXe5d2t{PDByIN88US=> MmnPSG1UVw>? MVPz[Y5{cXSrenXzJIh2dWGwIHLy[YF{fCClYX7j[ZIh[2WubDDsbY5meyC2bzDUVmFKVC2rbnT1Z4VlKGGyb4D0c5Nqew>? NUfMRpZNOTl6OU[0Olk>
Mesenchymal stem cells MWXLbY5ie2ViYYPzZZk> M{DzXlExKML3TR?= M2PTS2ROW09? NUCxS3VrcW6mdXPld{BiKHKxYoXzeEBidmRic4XzeIFqdmWmIFHNVGsh[WO2aY\heIlwdg>? MXiyOFExPDh5OR?=
Mesenchymal stem cells NVTWPYE1[3m2b4TvfIlkcXS7IHHzd4F6 NYPQSGc3OTByINM1US=> M3j0bmROW09? NVfINppq\GWlcnXhd4V{KHSqZTDNV2MheHKxbHnm[ZJifGmxbh?= NXvzUnBIOjRzMES4O|k>
MG-63 NELDeJBkgXSxdH;4bYNqfHliYYPzZZk> NXv3dmZ6OTBiwsXN MlHISG1UVw>? M2Hu[YlvcGmkaYTzJGgzVzJvSX7keYNm\CCRc4Tlc4Jt[XO2IFPlcIwhTGWjdHi= NVPzbJh5OjR7NkCzOlI>
MC3T3-E1 MlmyZ5l1d3SxeHnjbZR6KGG|c3H5 NEPnTYIyOCEEtV2= MWHEUXNQ M2nIUolvcGmkaYTzJGgzVzJvSX7keYNm\CCRc4Tlc4Jt[XO2IFPlcIwhTGWjdHi= NE\HToUzPDl4MEO2Ni=>
MG-63 Mo\MRZBweHSxc3nzJIF{e2G7 MUWxNEDDvU1? MUPEUXNQ M1i4[ZN2eHC{ZYPz[ZMhUDKRMj3JcoR2[2WmIF;zeIVw[myjc4SgR4VtdCCDcH;weI9{cXN? NHS5XIwzPDl4MEO2Ni=>
MC3T3-E1 MX\BdI9xfG:|aYOgZZN{[Xl? M1fTOlExKML3TR?= MVTEUXNQ MXzzeZBxemW|c3XzJGgzVzJvSX7keYNm\CCRc4Tlc4Jt[XO2IFPlcIwhSXCxcITvd4l{ MX[yOFk3ODN4Mh?=
MG-63 MoW0SpVv[3Srb36gZZN{[Xl? NGn0XowyOCEEtV2= MUDEUXNQ MVvhcIxmfmmjdHXzJHJQWyCjY3P1cZVt[XSrb36gZY5lKEGWUDDk[ZBt\XSrb36gZ4F2e2WmIHL5JGgzVzJ? MXmyOFk3ODN4Mh?=
MC3T3-E1 MlH3SpVv[3Srb36gZZN{[Xl? MUCxNEDDvU1? NFzCcJNFVVOR NGfqV5VidGyndnnheIV{KFKRUzDhZ4N2dXWuYYTpc44h[W6mIFHUVEBl\XCuZYTpc44h[2G3c3XkJIJ6KEh{T{K= M3\YPVI1QTZyM{[y
MG-63 Mn7pSpVv[3Srb36gZZN{[Xl? MXOxNEDDvU1? NGTkOpBFVVOR MYHmZYNqdGm2YYTld{BJOk9{LXnu[JVk\WRiYYX0c5Bp[We7IHHjeIl3[XSrb36= NWDoR3hTOjR7NkCzOlI>
MC3T3-E1 NFiwUFlHfW6ldHnvckBie3OjeR?= MY[xNEDDvU1? NFrMdItFVVOR MYnmZYNqdGm2YYTld{BJOk9{LXnu[JVk\WRiYYX0c5Bp[We7IHHjeIl3[XSrb36= MmXxNlQ6PjB|NkK=
PC3 MV3LbY5ie2ViYYPzZZk> NEnrNpUyODBiwsXN MWrEUXNQ MmLxeZBz\We3bHH0[ZMhfGinIHzleoVteyCxZjDBUXBMKGGwZDDBR2MheGixc4Doc5J6dGG2aX;u Ml\kNlU2QTRyNEO=
PC3M NWPFPWFQU2mwYYPlJIF{e2G7 M{LxTFExOCEEtV2= NIXmNFFFVVOR MVf1dJJm\3WuYYTld{B1cGVibHX2[Yx{KG:oIFHNVGsh[W6mIFHDR{BxcG:|cHjvdplt[XSrb36= NYrmdo9nOjV3OUSwOFM>
PC3 MkmzSpVv[3Srb36gZZN{[Xl? Mor5NVAxKML3TR?= NF30dlRFVVOR M{jsWolv\HWlZYOgVGk{Uy:vVF;SJJBifGi5YYnz M{LYd|I2PTl2MESz
PC3M NIPNe41HfW6ldHnvckBie3OjeR?= NYH0Om1rOTByINM1US=> NV63U25TTE2VTx?= MW\pcoR2[2W|IGDJN2swdVSRUjDwZZRpf2G7cx?= MnTRNlU2QTRyNEO=
PC3 M1rsd2dzd3e2aDDpcohq[mm2b4L5JIF{e2G7 NFXOZ4gyODBiwsXN MmnzSG1UVw>? MmfKd5VxeHKnc4Pld{Bxem:uaX\ldoF1cW:w M3jZOFI2PTl2MESz
PC3M MmjVS5Jwf3SqIHnubIljcXSxcomgZZN{[Xl? NGWze2YyODBiwsXN MUjEUXNQ NXLlUJdKe3WycILld5NmeyCycn;sbYZmemG2aX;u MnzrNlU2QTRyNEO=
MC3T3-E1 NVTIUFVmU2mwYYPlJIF{e2G7 MlLvNVAh|ryP MnXTSG1UVw>? M{LCeYlv\HWlZYOgd4lodmmoaXPhcpQhSU2SSzDhZ5RqfmG2aX;u MYeyOlg6OTh4Nh?=
MC3T3-E1 NGnLXW5Iem:5dHigbY5pcWKrdH;yfUBie3OjeR?= M3rEeFExKM7:TR?= NH:0cIhFVVOR MUDpcohq[mm2czDE[ZgucW6mdXPl[EBwe3Snb3LsZZN1KGOnbHyg[IVifGh? MXeyOlg6OTh4Nh?=
MC3T3-E1 NF\6[plHfW6ldHnvckBie3OjeR?= MkjaNVAh|ryP MXLEUXNQ MXvpcohq[mm2czDE[ZgucW6mdXPl[EBwgGmmYYTpeoUhe3S{ZYPz M1f3TFI3QDlzOE[2

... Click to View More Cell Line Experimental Data

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

プロトコル (参考用のみ)

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 M nonessential amino acids, 5 μg/ml transferrin, 100 nM dexamethasone, 100 nM insulin and 25 μg/ml gentamycin. After 4 hr medium is replaced with medium as described above but without FBS and containing 100 nM triiodothyronine (T3). Following a 16 hr, 37°C incubation, the incubation medium is removed and replaced with medium containing 14C acetate (2 μCi/ml) and AICAR or test compounds at the indicated concentrations. Cells are incubated 4 hr at 37°C then the plates are rinsed with PBS. The final wash is replaced with Microscint20 and radioactivity incorporated into fatty acid monitors on a Wallac Microbeta plate reader.

細胞アッセイ:

[3]

細胞株 MEF cells
濃度 300 μM
反応時間 24 hours
実験の流れ

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
投与方法 Administered via i.p.

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

SpeciesMouseRatRabbitGuinea pigHamsterDogMonkeyBaboon
Weight (kg)0.020.151.80.40.0810312
Body Surface Area (m2)0.0070.0250.150.050.020.50.240.6
Km factor361285201220
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 solvent
別名 N/A
溶解度 (25°C) * In vitro DMSO 72 mg/mL (199.78 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-

カスタマーフィードバック (4)


Click to enlarge
Rating
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).

Click to enlarge
Rating
Source J Lipid Res, 2014, 55(7), 1254-1266. A-769662 purchased from Selleck
Method Immunoblotting
Cell Lines Ldlr-/- mice
Concentrations 30 mg/kg
Incubation Time 90 min
Results Mice were also injected with the potent synthetic AMPK activator A-76966, which increased AMPK and ACC phosphorylation ~ 2-fold.

Click to enlarge
Rating
Source Pharmacol Res, 2014, 81, 34-43. A-769662 purchased from Selleck
Method H<sub>2</sub>S-selective sensor
Cell Lines
Concentrations 0-250 uM
Incubation Time 10 min
Results Synthetic AMPK activator, A-769662, increased AMPK phosphorylation in a concentration-dependent manner. AMPK inhibitor, compound C, had no effect on AMPK phosphorylation in the absence of A-769662 but abolished enzyme stimulation induced by this activator.

Click to enlarge
Rating
Source Biochem Biophys Res Commun, 2013, 437(1), 1-6. A-769662 purchased from Selleck
Method Western blot
Cell Lines PANC-1 cells
Concentrations 10 uM
Incubation Time 2 h
Results Western blot results demonstrated that belinostat induced AMPK activation in a time-dependent manner. It showed that belinostat induced AMPK activation in a dose-dependent manner, and significant AMPK/ACC phosphorylation was observed by 1 or 10 uM of belinostat treatment. Two well-known AMPK activators AICAR and A-769662 also promoted AMPK activation in PANC-1 cells.

文献中の引用 (6)

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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