KU-0063794

Catalog No.S1226

KU-0063794 Chemical Structure

Molecular Weight(MW): 465.54

KU-0063794 is a potent and highly specific dual-mTOR inhibitor of mTORC1 and mTORC2 with IC50 of ~10 nM in cell-free assays; no effect on PI3Ks.

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In DMSO USD 180 In stock
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Cited by 30 Publications

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Biological Activity

Description KU-0063794 is a potent and highly specific dual-mTOR inhibitor of mTORC1 and mTORC2 with IC50 of ~10 nM in cell-free assays; no effect on PI3Ks.
Targets
mTORC1 [1]
(Cell-free assay)
mTORC2 [1]
(Cell-free assay)
~10 nM ~10 nM
In vitro

Compared with the mTOR inhibitor PP242, KU-0063794 exhibits higher specificity for mTOR, as being inactive against PI3Ks or 76 other kinases. In HEK-293 cells, KU-0063794 at 30 nM is sufficient to rapidly ablate S6K1 activity by blocking the phosphorylation of the hydrophobic motif (Thr389) and subsequently the phosphorylation of the T-loop residue (Thr229). In case of IGF1 stimulation of serum-starved HEK-293 cells, 300 nM of KU-0063794 is needed to inhibit the S6K1 activity by ~90%. KU-0063794 at 100-300 nM also completely inhibits the amino-acid-induced phosphorylation of S6K1 and S6 protein. Similar to S6K1, KU-0063794 inhibits the phosphorylation of mTORC1 at Ser2448 and mTORC2 at Ser2481 in a dose-dependent and time-dependent manner. In the presence of serum or following IGF1 stimulation, KU-0063794 induces a dose-dependent inhibition of the activity and phosphorylation of Akt at Ser473 and unexpected Thr308 as well as the phosphorylation of the Akt substrates PRAS40 at Thr246, GSK3α/GSK3β at Ser21/Ser9 and Foxo-1/3a at Thr24/Thr32. KU-0063794 but not rapamycin inhibits SGK1 activity and Ser422 phosphorylation as well as its physiological substrate NDGR1 in a dose-dependent manner, to the same extent as S6K1 and Akt phosphorylation, whereas KU-0063794 dose not inhibit phorbol ester induced ERK or RSK phosphorylation and RSK activation. Compared with rapamycin, KU-0063794 exhibits more significant potency to induce the complete dephosphorylation of 4E-BP1 at Thr37, Thr46 and Ser65. KU-0063794 inhibits cell growth of both wild-type and mLST8-deficient MEFs and induces a G1 cell cycle arrest, more significantly than rapamycin. [1]

Cell Data
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
HepG2  NIXQXXZE\WyuIG\pZYJqdGm2eTDBd5NigQ>? MX2wMlHjiJN3MNMg{txO M4K2NlczKGh? Mlnk[IVkemWjc3XzJINmdGxidnnhZoltcXS7IHnuJIEh\G:|ZTDk[ZBmdmSnboSgcYFvdmW{ NWHaTplSOjZ{N{i4NVk>
HepG2  M1m2ZWNwdG:weTDGc5Ju[XSrb36gRZN{[Xl? Mon6NgKBmzVywrFOwG0> MVuxNEBl NVvHXpFm\GWlcnXhd4V{KHSqZTDueY1j\XJib3[geoli[mynIFjldGczKGOxbH;ubYV{yqC|aXfubYZq[2GwdHz5 NFXJeokzPjJ5OEixPS=>
HepG2  MU\BdI9xfG:|aYOgRZN{[Xl? NETJU3kxNjIkgKO1NOKh|ryP NXry[3NZPDhiaB?= MXfpcoR2[2W|IHHwc5B1d3OrczDpckBiKGSxc3Wg[IVx\W6mZX70JI1idm6nch?= NYS1WplSOjZ{N{i4NVk>
HepG2  NF3H[GpHfW6ldHnvckBCe3OjeR?= MnHZOU8yOCEQvF2= MlLBNlQhcA>? NI\NT41lemGvYYTpZ4FtdHliaX7obYJqfHNicHjvd5Bpd3K7bHH0bY9vKG:oIFHLWEBifCCVZYKtOFc{ MWKyOlI4QDhzOR?=
HepG2  MYfGeY5kfGmxbjDBd5NigQ>? MUC1M|ExKM7:TR?= MUWyOEBp NV3IZXBM\G:5boLl[5Vt[XSnczD0bIUhdGW4ZXzzJGhKTjIQsTDhcoQh[3mlbHnuJGQyyqB? MYGyOlI4QDhzOR?=
HepG2  MWfGeY5kfGmxbjDBd5NigQ>? M4O3WlAvOeLCk{WwxsDPxE1? MYWyOEBp M{HmZolv\HWlZYOgdFYzKGSxd37y[Yd2dGG2aX;uMEBD\WOuaX6tNUBmgHC{ZYPzbY9vKGGwZDDMR|NDNUlidH:gUGM{Si2LSTDjc453\XK|aX;uJIlvKGFiZH;z[UBl\XCnbnTlcpQhdWGwbnXy MoXVNlYzPzh6MUm=
HepG3  NYe0ZolTTnWwY4Tpc44hSXO|YYm= M{\UZVAvOeLCk{WwxsDPxE1? NUjwVJRxPDhiaB?= NI\nXGZqdmS3Y3XzJINmdGxiYYX0c5Bp[We7IHnuJIEh\G:|ZTDk[ZBmdmSnboSgcYFvdmW{ M4S4R|I3Ojd6OEG5
AGS NHWxXFlIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MYHJR|UxRTF3LkCgxtEhOi57MTFOwG0> NILzbWEzPDV7N{S3PC=>
HGC27 Mn3XS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MlLtTWM2OD1zNT6wJOKyKDRwOEKg{txO M{fQeFI1PTl5NEe4
MKN45 MXvHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NX;TeVhZUUN3ME2wMlgzKMLzIECuNFEh|ryP M37hfVI1PTl5NEe4
NUGC4 NXTEVHJTT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MYTJR|UxRTJwOUOgxtEhOC5|MTFOwG0> NEPFTIwzPDV7N{S3PC=>
PC9 MWfHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NI\WXHE4OiCq M1u2SmlEPTB;MUCuNVXDuTBwNkKgcm0> NEezU4UzOzh5NEi4NC=>
PC9GR MWjHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M{PvOlczKGh? NX7mT2FbUUN3ME22MlIyyrFzLkOwJI5O NF:2XWczOzh5NEi4NC=>
H1650 M3P1fmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MnT0O|IhcA>? NUXPbFd{UUN3ME23MlYyyrFyLk[yJI5O MmLSNlM5PzR6OEC=
H1975 NUf2fItVT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MmDEO|IhcA>? NWfWeYd3UUN3ME2xNU4yPcLzMD65N{BvVQ>? Mn\jNlM5PzR6OEC=
PC9 NXL5TI5kTnWwY4Tpc44hSXO|YYm= NH;6PHUyOC5zNTDuUS=> NVGxTodmPzJiaB?= M{TnWolvcGmkaYTzJI1VV1JicHjvd5Bpd3K7bHH0bY9vKHO2YYT1d:Kh NVT1Z5pzOjN6N{S4PFA>
PC9GR Mmj4SpVv[3Srb36gRZN{[Xl? MkfIOk4zOSCwTR?= MoPrO|IhcA>? M13EfIlvcGmkaYTzJI1VV1JicHjvd5Bpd3K7bHH0bY9vKHO2YYT1d:Kh NFW5VnQzOzh5NEi4NC=>
H1650 M3TN[2Z2dmO2aX;uJGF{e2G7 Mon0O{43OSCwTR?= MmHlO|IhcA>? Ml3FbY5pcWKrdIOgcXRQWiCyaH;zdIhwenmuYYTpc44he3SjdIXzxsA> NV;IWG1kOjN6N{S4PFA>
H1975 MWHGeY5kfGmxbjDBd5NigQ>? MnHnNVEvOTVibl2= NWfCTHREPzJiaB?= MWnpcohq[mm2czDtWG9TKHCqb4PwbI9zgWyjdHnvckB{fGG2dYRCpC=> MYeyN|g4PDh6MB?=
PC9 MV\GeY5kfGmxbjDBd5NigQ>? Mn;uNVAvOTVibl2= MXW3NkBp NWXqTIx5cW6qaXLpeJMheGixc4Doc5J6dGG2aX;uJI9nKHB5MGO2Ty=> NG\aUFEzOzh5NEi4NC=>
PC9GR M1HiNWZ2dmO2aX;uJGF{e2G7 MWm2MlIyKG6P NHrHUJo4OiCq NXzPXYtIcW6qaXLpeJMheGixc4Doc5J6dGG2aX;uJI9nKHB5MGO2Ty=> MVmyN|g4PDh6MB?=
H1650 NUTNNGxjTnWwY4Tpc44hSXO|YYm= NF\RVXI4NjZzIH7N NXXIVJlwPzJiaB?= NWjHOWdXcW6qaXLpeJMheGixc4Doc5J6dGG2aX;uJI9nKHB5MGO2Ty=> MXiyN|g4PDh6MB?=
H1975 NUfyOWhlTnWwY4Tpc44hSXO|YYm= NFm5Rm0yOS5zNTDuUS=> NUPFcG1MPzJiaB?= NFzySHVqdmirYnn0d{BxcG:|cHjvdplt[XSrb36gc4YheDdyU{\L M4jYPFI{QDd2OEiw
LNCaP MXzD[YxtKF[rYXLpcIl1gSCDc4PhfS=> M4DkZlAuOTBizszN NH33XJIzPCCqwrC= NEm3SJNl\WO{ZXHz[ZMh[2WubDD2bYFjcWyrdImgbY4h[SCmb4PlJIRmeGWwZHXueEBu[W6wZYK= NXXoR3R2OjN6NEC2NFU>
PC-3 NH:2SZlE\WyuIG\pZYJqdGm2eTDBd5NigQ>? NH7ie3oxNTFyIN88US=> NXXOdIY4OjRiaNMg MYjk[YNz\WG|ZYOgZ4VtdCC4aXHibYxqfHliaX6gZUBld3OnIHTldIVv\GWwdDDtZY5v\XJ? NFrtOJIzOzh2ME[wOS=>
MDA-MB-468  MXjD[YxtKF[rYXLpcIl1gSCDc4PhfS=> MYewMVExKM7:TR?= Ml\nNlQhcMLi M{TlVYRm[3KnYYPld{Bk\WyuII\pZYJqdGm2eTDpckBiKGSxc3Wg[IVx\W6mZX70JI1idm6nch?= NI\MPI8zOzh2ME[wOS=>
LNCaP NFHVZVBHfW6ldHnvckBCe3OjeR?= MVOyNFDjiJN6MECgcm0> Mo\3NlQhcMLi NEGydYxl\WO{ZXHz[ZMhfGinIIDoc5NxcG:{eXzheIlwdiCuZY\lcEBw\iCyN{DTOmshcW5iYTDkc5NmKGSncHXu[IVvfCCvYX7u[ZI> NHnqdZEzOzh2ME[wOS=>
PC-3 NIDxTWxHfW6ldHnvckBCe3OjeR?= MoD2NlAx6oDVOECwJI5O NHz0dFgzPCCqwrC= MVXk[YNz\WG|ZYOgeIhmKHCqb4PwbI9zgWyjdHnvckBt\X[nbDDv[kBxPzCVNlugbY4h[SCmb4PlJIRmeGWwZHXueEBu[W6wZYK= MViyN|g1ODZyNR?=
MDA-MB-468  NYTnVXpLTnWwY4Tpc44hSXO|YYm= MV6yNFDjiJN6MECgcm0> NULUS5Q1OjRiaNMg NV\xflJ2\GWlcnXhd4V{KHSqZTDwbI9{eGixconsZZRqd25ibHX2[Ywhd2ZicEewV|ZMKGmwIHGg[I9{\SCmZYDlcoRmdnRibXHucoVz M4X1NFI{QDRyNkC1
Caki-1  Mke1SpVv[3Srb36gRZN{[Xl? NVX0VHptOTByLUKwNFAhdk1? M4nmV|ExNTF6MDDtbY4> MlnKSG1UVw>? MWDpcohq[mm2czDic5RpKG2WT2LDNUBidmRibWTPVmMzKGG|IHnu[Ilk[XSnZDDifUB1cGViZHXjdoVie2ViaX6gdIhwe3Cqb4L5cIF1cW:wIH;mJIRwf26|dILlZY0h\W[oZXP0c5J{ NXjJNXlNOjN|NEm5PFk>
786-O M3Sxb2Z2dmO2aX;uJGF{e2G7 MmjjNVAxNTJyMECgcm0> MWqxNE0yQDBibXnu MVnEUXNQ M4XXNYlvcGmkaYTzJIJwfGhibWTPVmMyKGGwZDDtWG9TSzJiYYOgbY5lcWOjdHXkJIJ6KHSqZTDk[YNz\WG|ZTDpckBxcG:|cHjvdplt[XSrb36gc4Yh\G:5boP0doVidSCnZn\lZ5RwenN? Mln1NlM{PDl7OEm=
Caki-1  MVHD[YxtKF[rYXLpcIl1gSCDc4PhfS=> MVKzNFAuPDByMDDuUS=> MYKyOE06PiCq MnvlSG1UVw>? M3PNV5N2eHC{ZYPz[ZMhfGinIHPlcIwhfmmjYnnsbZR6KGmwIHLveIghfGmvZTDhcoQh\G:|ZTDk[ZBmdmSnboSgcYFvdmW{ MV[yN|M1QTl6OR?=
786-O NFrvV|RE\WyuIG\pZYJqdGm2eTDBd5NigQ>? NWT4R5RkOzByLUSwNFAhdk1? NWHmSllHOjRvOU[gbC=> NHXkTnBFVVOR NFzaeJF{fXCycnXzd4V{KHSqZTDj[YxtKH[rYXLpcIl1gSCrbjDic5RpKHSrbXWgZY5lKGSxc3Wg[IVx\W6mZX70JI1idm6nch?= NEnTO4czOzN2OUm4PS=>
Caki-1  M2nSbGZ2dmO2aX;uJGF{e2G7 MlXsNkDDvU1? NVjOTHVuPzJiaB?= NXfkTmt2TE2VTx?= NHHTTVBqdmS3Y3XzJGcyKGOnbHygZ5lkdGViYYLy[ZN1KGGwZDDheZRweGijZ4m= M2jCUFI{OzR7OUi5
786-O M4PWZ2Z2dmO2aX;uJGF{e2G7 NHvFU24zKML3TR?= NFS2coQ4OiCq NVSyeIh{TE2VTx?= NF35c|BqdmS3Y3XzJGcyKGOnbHygZ5lkdGViYYLy[ZN1KGGwZDDheZRweGijZ4m= MWCyN|M1QTl6OR?=

... Click to View More Cell Line Experimental Data

Assay
Methods Test Index PMID
Western blot
p-S6K / S6K / p-4E-BP1 / E7 / E6 / p53 ; 

PubMed: 28115701     


Normoxic HPV-positive cancer cells were treated for 24 h with 0.5, 1.0, or 5 μM KU-0063794 (KU) or 50 nM rapamycin. Shown are immunoblots of P-S6K, S6K, P-4E-BP1, 4E-BP1, HPV16/18 E6/E7, and p53 protein levels. DMSO served as a solvent control; β-actin, as a loading control.

p-mTOR; 

PubMed: 24262658     


Inhibition of mTOR pathway by mTOR kinase inhibitors. MCC-2 cells were treated with WYE354 (3 μM), PP242 (2.5 μM), and Ku-0063794 (5 μM) for 24h, respectively. Lysates were prepared and subjected to immunoblotting analysis with indicated antibodies. 

28115701 24262658
In vivo Ku0063794 inhibits tumor growth and mTOR signaling in a preclinical renal cell carcinoma model. However, Ku0063794 was not more effective than temsirolimus in the animal study. A possible explanation for lack of greater activity in vivo for Ku0063794 is that temsirolimus has important effects on the tumor microenvironment. Temsirolimus decreased angiogenesis in the xenograft tumors while Ku0063794 did not. Temsirolimus treated tumors expressed less VEGF and PDGF than Ku0063794 treated tumors, thus stimulating less angiogenesis[2].

Protocol

Kinase Assay:

[1]

- Collapse

mTOR complexes kinase assays:

HEK-293 cells are freshly lysed in Hepes lysis buffer. Lysate (1-4 mg) is pre-cleared by incubating with 5-20 μL of Protein G-Sepharose conjugated to pre-immune IgG. The lysate extracts are then incubated with 5-20 μL of Protein G-Sepharose conjugated to 5-20 μg of either anti-Rictor or anti-Raptor antibody, or pre-immune IgG. All antibodies are covalently conjugated to Protein G-Sepharose. Immunoprecipitations are carried out for 1 hour at 4 °C on a vibrating platform. The immunoprecipitates are washed four times with Hepes lysis buffer, followed by two washes with Hepes kinase buffer. For Raptor immunoprecipitates used for phosphorylating S6K1, for the initial two wash steps the buffer includes 0.5 M NaCl to ensure optimal kinase activity. GST-Akt1 is isolated from serum-deprived HEK-293 cells incubated with PI-103 (1 μM for 1 hour). GST-S6K1 is purified from serum-deprived HEK-293 cells incubated with rapamycin (0.1 μM for 1 hour). mTOR reactions are initiated by adding 0.1 mM ATP and 10 mM MgCl2 in the presence of various concentrations of KU-0063794 and GST-Akt1 (0.5 μg) or GST-S6K1 (0.5 μg). Reaction are carried out for 30 minutes at 30 °C on a vibrating platform and stopped by addition of SDS sample buffer. Reaction mixtures are then filtered through a 0.22-μm-poresize Spin-X filter and samples are subjected to electrophoresis and immunoblot analysis with the indicated antibodies.
Cell Research:

[1]

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  • Cell lines: Wild-type and mLST8 deficient MEFs
  • Concentrations: Dissolved in DMSO, final concentration ~3 μM
  • Incubation Time: 24, 48, and 72 hours
  • Method:

    Cells are treated with KU-0063794 for 24, 48, and 72 hours, and the medium is changed every 24 hours with freshly dissolved KU-0063794. For the measurement of cell growth, cells are washed once with PBS, and fixed in 4% (v/v) paraformaldehyde in PBS for 15 minutes. After washing once with water, the cells are stained with 0.1% Crystal Violet in 10% ethanol for 20 minutes and washed three times with water. Crystal Violet is extracted from cells with 0.5 mL of 10% (v/v) ethanoic (acetic) acid for 20 minutes. The eluate is then diluted 1:10 in water and absorbance at 590 nm is quantified. For the assessment of cell cycle distribution, cells are harvested by trypsinization, washed once in PBS, and re-suspended in ice-cold aq. 70% (v/v) ethanol. Cells are washed twice in PBS plus 1% (w/v) BSA and stained for 20 minutes in PBS plus 0.1% (v/v) Triton X-100 containing 50 g/mL propidium iodide and 50 g/mL RNase A. The DNA content of cells is determined using a FACSCalibur flow cytometer and CellQuest software. Red fluorescence (585 nm) is acquired on a linear scale, and pulse width analysis is used to exclude doublets. Cell-cycle distribution is determined using FlowJo software.


    (Only for Reference)
Animal Research:

[2]

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  • Animal Models: Nu/Nu nude mice
  • Formulation: one part DMSO and then diluted (200 µg/100 µl) with 4 parts PEG1500 (50% (w/v) in 75 mM Hepes, pH 8.0
  • Dosages: 8 mg/kg
  • Administration: i.p.
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 16 mg/mL (34.36 mM)
Water Insoluble
Ethanol Insoluble
In vivo Add solvents to the product individually and in order(Data is from Selleck tests instead of citations):
30% PEG400+0.5% Tween80+5% propylene glycol
For best results, use promptly after mixing.
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.

Chemical Information

Molecular Weight 465.54
Formula

C25H31N5O4

CAS No. 938440-64-3
Storage powder
in solvent
Synonyms N/A

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID