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 41 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  NYO3XW1nS2WubDDWbYFjcWyrdImgRZN{[Xl? MVOwMlHjiJN3MNMg{txO MWm3NkBp MWDk[YNz\WG|ZYOgZ4VtdCC4aXHibYxqfHliaX6gZUBld3OnIHTldIVv\GWwdDDtZY5v\XJ? M1\YU|I3Ojd6OEG5
HepG2  MkjJR49td267IF\vdo1ifGmxbjDBd5NigQ>? MXWx5qCUPTEEoN88US=> NFPEOXcyOCCm NF;MPGxl\WO{ZXHz[ZMhfGinIH71cYJmeiCxZjD2bYFjdGViSHXwS|Ih[2:ub37p[ZPDqHOrZ37p[olk[W62bIm= MXSyOlI4QDhzOR?=
HepG2  NXr5ZoZXSXCxcITvd4l{KEG|c3H5 MmP6NE4y6oDVNUFCpO69VQ>? M1uweFQ5KGh? MkPkbY5lfWOnczDhdI9xfG:|aYOgbY4h[SCmb4PlJIRmeGWwZHXueEBu[W6wZYK= MWOyOlI4QDhzOR?=
HepG2  MX3GeY5kfGmxbjDBd5NigQ>? Mni4OU8yOCEQvF2= MX[yOEBp NXu4fGFK\HKjbXH0bYNidGy7IHnubIljcXS|IIDoc5NxcG:{eXzheIlwdiCxZjDBT3Qh[XRiU3XyMVQ4Ow>? NW\xNmJqOjZ{N{i4NVk>
HepG2  MkW2SpVv[3Srb36gRZN{[Xl? MX61M|ExKM7:TR?= NVnRT|FCOjRiaB?= NHXGVlJld3ewcnXneYxifGW|IITo[UBt\X[nbIOgTGlHOc7zIHHu[EBkgWOuaX6gSFHDqA>? NXLXSY43OjZ{N{i4NVk>
HepG2  M{DzWGZ2dmO2aX;uJGF{e2G7 Mmr3NE4y6oDVNUFCpO69VQ>? NW\oXoFOOjRiaB?= MUPpcoR2[2W|IIC2NkBld3ewcnXneYxifGmxbjygRoVkdGmwLUGg[ZhxemW|c3nvckBidmRiTFOzRk1KKHSxIFzDN2IuUUliY3;ueoVze2mxbjDpckBiKGSxc3Wg[IVx\W6mZX70JI1idm6nch?= NGfNb|gzPjJ5OEixPS=>
HepG3  MYLGeY5kfGmxbjDBd5NigQ>? MkTtNE4y6oDVNUFCpO69VQ>? NH\Ddok1QCCq M3zJb4lv\HWlZYOgZ4VtdCCjdYTvdIhi\3liaX6gZUBld3OnIHTldIVv\GWwdDDtZY5v\XJ? NFnib3UzPjJ5OEixPS=>
AGS NV7BdoNUT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M3TzSGlEPTB;MUWuNEDDuSB{LkmxJO69VQ>? NXmxW4llOjR3OUe0O|g>
HGC27 NVjnfWpUT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NGTVOY9KSzVyPUG1MlAhyrFiND64NkDPxE1? NE\Mco8zPDV7N{S3PC=>
MKN45 NELWVXBIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M1PUWGlEPTB;MD64NkDDuSByLkCxJO69VQ>? M2nvXVI1PTl5NEe4
NUGC4 NIWzXWlIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NWewW21[UUN3ME2yMlk{KMLzIECuN|Eh|ryP NX\xfoxHOjR3OUe0O|g>
PC9 M1WxOmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MXS3NkBp NWHtUGNFUUN3ME2xNE4yPcLzMD62NkBvVQ>? M3PUNlI{QDd2OEiw
PC9GR NV\rWJk6T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MWq3NkBp NFHDRo9KSzVyPU[uNlHDuTFwM{Cgcm0> NF;Q[4EzOzh5NEi4NC=>
H1650 M{PyfWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M4L1WVczKGh? M2r5WGlEPTB;Nz62NeKyOC54MjDuUS=> MYmyN|g4PDh6MB?=
H1975 M3\0b2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M3O0bVczKGh? NGfKXFFKSzVyPUGxMlE2yrFyLkmzJI5O M{LuNVI{QDd2OEiw
PC9 NHTqTY5HfW6ldHnvckBCe3OjeR?= M3i1SVExNjF3IH7N NFfOO|c4OiCq MUPpcohq[mm2czDtWG9TKHCqb4PwbI9zgWyjdHnvckB{fGG2dYRCpC=> NYDYdJRYOjN6N{S4PFA>
PC9GR NVTkbW96TnWwY4Tpc44hSXO|YYm= NIDDbIY3NjJzIH7N Mn;yO|IhcA>? NIm3enJqdmirYnn0d{BuXE:UIIDoc5NxcG:{eXzheIlwdiC|dHH0eZPDqA>? MY[yN|g4PDh6MB?=
H1650 M16zW2Z2dmO2aX;uJGF{e2G7 MWS3MlYyKG6P MVe3NkBp NI\OO5lqdmirYnn0d{BuXE:UIIDoc5NxcG:{eXzheIlwdiC|dHH0eZPDqA>? M3XZRlI{QDd2OEiw
H1975 NYnCbYR[TnWwY4Tpc44hSXO|YYm= NYX6UmZkOTFwMUWgcm0> M{HofFczKGh? NICweZZqdmirYnn0d{BuXE:UIIDoc5NxcG:{eXzheIlwdiC|dHH0eZPDqA>? MVOyN|g4PDh6MB?=
PC9 NVvz[YdsTnWwY4Tpc44hSXO|YYm= M1vqWVExNjF3IH7N NHHPUFg4OiCq M{nlfIlvcGmkaYTzJJBpd3OyaH;yfYxifGmxbjDv[kBxPzCVNlu= M17rT|I{QDd2OEiw
PC9GR M1LWO2Z2dmO2aX;uJGF{e2G7 NX\NeYtYPi5{MTDuUS=> NUPpWlhiPzJiaB?= Mo\lbY5pcWKrdIOgdIhwe3Cqb4L5cIF1cW:wIH;mJJA4OFN4Sx?= NV:yfIlzOjN6N{S4PFA>
H1650 NYHtU401TnWwY4Tpc44hSXO|YYm= M4rSc|cvPjFibl2= NYPwb3E5PzJiaB?= MVzpcohq[mm2czDwbI9{eGixconsZZRqd25ib3[gdFcxWz[N NFOwW|MzOzh5NEi4NC=>
H1975 M3y5SWZ2dmO2aX;uJGF{e2G7 M3rKblEyNjF3IH7N M1u3fVczKGh? Moi1bY5pcWKrdIOgdIhwe3Cqb4L5cIF1cW:wIH;mJJA4OFN4Sx?= NYDNZYwzOjN6N{S4PFA>
LNCaP MnvkR4VtdCCYaXHibYxqfHliQYPzZZk> NYP2OXZtOC1zMDFOwG0> NGTCZoQzPCCqwrC= Mlu5[IVkemWjc3XzJINmdGxidnnhZoltcXS7IHnuJIEh\G:|ZTDk[ZBmdmSnboSgcYFvdmW{ NG\Wc3MzOzh2ME[wOS=>
PC-3 MVPD[YxtKF[rYXLpcIl1gSCDc4PhfS=> NH3FOJIxNTFyIN88US=> Ml;ZNlQhcMLi MnzO[IVkemWjc3XzJINmdGxidnnhZoltcXS7IHnuJIEh\G:|ZTDk[ZBmdmSnboSgcYFvdmW{ MUCyN|g1ODZyNR?=
MDA-MB-468  NVXVOXJLS2WubDDWbYFjcWyrdImgRZN{[Xl? MmnTNE0yOCEQvF2= MYSyOEBpyqB? M3rsb4Rm[3KnYYPld{Bk\WyuII\pZYJqdGm2eTDpckBiKGSxc3Wg[IVx\W6mZX70JI1idm6nch?= NH7CdYgzOzh2ME[wOS=>
LNCaP M4K5VmZ2dmO2aX;uJGF{e2G7 MV2yNFDjiJN6MECgcm0> M{K5[|I1KGkEoB?= M2rRUYRm[3KnYYPld{B1cGVicHjvd5Bpd3K7bHH0bY9vKGyndnXsJI9nKHB5MGO2T{BqdiCjIHTvd4Uh\GWyZX7k[Y51KG2jbn7ldi=> Mnj0NlM5PDB4MEW=
PC-3 M4LHdmZ2dmO2aX;uJGF{e2G7 M3rPe|IxOOLCk{iwNEBvVQ>? M4LKbVI1KGkEoB?= NE\FcIhl\WO{ZXHz[ZMhfGinIIDoc5NxcG:{eXzheIlwdiCuZY\lcEBw\iCyN{DTOmshcW5iYTDkc5NmKGSncHXu[IVvfCCvYX7u[ZI> MXGyN|g1ODZyNR?=
MDA-MB-468  MWLGeY5kfGmxbjDBd5NigQ>? NXnUPGR3OjBy4pETPFAxKG6P NU\rbndXOjRiaNMg M1H0Z4Rm[3KnYYPld{B1cGVicHjvd5Bpd3K7bHH0bY9vKGyndnXsJI9nKHB5MGO2T{BqdiCjIHTvd4Uh\GWyZX7k[Y51KG2jbn7ldi=> NXTDeVBzOjN6NEC2NFU>
Caki-1  MnHFSpVv[3Srb36gRZN{[Xl? M1vtR|ExOC1{MECwJI5O M1W1OlExNTF6MDDtbY4> MYfEUXNQ MWHpcohq[mm2czDic5RpKG2WT2LDNUBidmRibWTPVmMzKGG|IHnu[Ilk[XSnZDDifUB1cGViZHXjdoVie2ViaX6gdIhwe3Cqb4L5cIF1cW:wIH;mJIRwf26|dILlZY0h\W[oZXP0c5J{ MojrNlM{PDl7OEm=
786-O NI\jSIpHfW6ldHnvckBCe3OjeR?= MVOxNFAuOjByMDDuUS=> MVexNE0yQDBibXnu NVnBS5FyTE2VTx?= MlzMbY5pcWKrdIOgZo91cCCvVF;SR|Eh[W6mIH3UU3JEOiCjczDpcoRq[2G2ZXSgZpkhfGinIHTlZ5Jm[XOnIHnuJJBpd3OyaH;yfYxifGmxbjDv[kBld3ewc4Ty[YFuKGWoZnXjeI9zew>? MXGyN|M1QTl6OR?=
Caki-1  NWrVfoxPS2WubDDWbYFjcWyrdImgRZN{[Xl? MXKzNFAuPDByMDDuUS=> MXKyOE06PiCq M1nzZ2ROW09? MWXzeZBxemW|c3XzJJRp\SClZXzsJJZq[WKrbHn0fUBqdiCkb4ToJJRqdWViYX7kJIRwe2ViZHXw[Y5l\W62IH3hco5meg>? NHPmco8zOzN2OUm4PS=>
786-O NVq5XW5vS2WubDDWbYFjcWyrdImgRZN{[Xl? NH7XepU{ODBvNECwNEBvVQ>? MUeyOE06PiCq NEHqPJBFVVOR MUfzeZBxemW|c3XzJJRp\SClZXzsJJZq[WKrbHn0fUBqdiCkb4ToJJRqdWViYX7kJIRwe2ViZHXw[Y5l\W62IH3hco5meg>? NFfPcpkzOzN2OUm4PS=>
Caki-1  MX3GeY5kfGmxbjDBd5NigQ>? NVvMRXRFOiEEtV2= M{PSVlczKGh? MVHEUXNQ NXTWWnp[cW6mdXPld{BIOSClZXzsJIN6[2ynIHHydoV{fCCjbnSgZZV1d3CqYXf5 M4r5ZlI{OzR7OUi5
786-O NIfaTohHfW6ldHnvckBCe3OjeR?= NVLaTVNpOiEEtV2= MkK5O|IhcA>? NHK5d2tFVVOR M3HUNIlv\HWlZYOgS|Eh[2WubDDjfYNt\SCjcoLld5Qh[W6mIHH1eI9xcGGpeR?= M1LHSlI{OzR7OUi5

... 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]

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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