GSK690693

Catalog No.S1113

GSK690693 Chemical Structure

Molecular Weight(MW): 425.48

GSK690693 is a pan-Akt inhibitor targeting Akt1/2/3 with IC50 of 2 nM/13 nM/9 nM in cell-free assays, also sensitive to the AGC kinase family: PKA, PrkX and PKC isozymes. Phase 1.

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In DMSO USD 221 In stock
USD 170 In stock
USD 770 In stock
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Cited by 45 Publications

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Biological Activity

Description GSK690693 is a pan-Akt inhibitor targeting Akt1/2/3 with IC50 of 2 nM/13 nM/9 nM in cell-free assays, also sensitive to the AGC kinase family: PKA, PrkX and PKC isozymes. Phase 1.
Targets
Akt1 [1]
(Cell-free assay)		 PKCη [1]
(Cell-free assay)		 PKCθ [1]
(Cell-free assay)		 PrkX [1]
(Cell-free assay)		 Akt3 [1]
(Cell-free assay)
2 nM 2 nM 2 nM 5 nM 9 nM
In vitro

GSK690693 is very selective for the Akt isoforms versus the majority of kinases in other families. However, GSK690693 is less selective for members of the AGC kinase family including PKA, PrkX, and PKC isozymes with IC50 of 24 nM, 5 nM, and 2-21 nM, respectively. GSK690693 also potently inhibits AMPK and DAPK3 from the CAMK family with IC50 of 50 nM and 81 nM, respectively, and PAK4, 5, and 6 from the STE family with IC50 of 10 nM, 52 nM, and 6 nM, respectively. GSK690693 inhibits the phosphorylation of GSK3β in tumor cells with IC50 ranging from 43 nM to 150 nM. GSK690693 treatment leads to a dose-dependent increase in the nuclear accumulation of the transcription factor FOXO3A. GSK690693 potently inhibits the proliferation of T47D, ZR-75-1, BT474, HCC1954, MDA-MB-453, and LNCaP cells with IC50 of 72 nM, 79 nM, 86 nM, 119 nM, 975 nM, and 147 nM, respectively. GSK690693 treatment induces apoptosis at concentrations >100 nM in both LNCaP and BT474 cells. [1] Consistent with the role of AKT in cell survival, GSK690693 induces apoptosis in sensitive ALL cell lines. [2]
Cell Data
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
human LNCaP cells NHLJcWJRem:uaX\ldoF1cW:wIHHzd4F6 MnX6RY51cXC{b3zp[oVz[XSrdnWgZYN1cX[rdImgZYdicW6|dDDoeY1idiCOTlPhVEBk\WyuczygTWM2OD1{MDDuUS=> M1GyZlE5QDByN{[z
human BT474 cells M1L5eXBzd2yrZnXyZZRqd25iYYPzZZk> MlfXRY51cXC{b3zp[oVz[XSrdnWgZYN1cX[rdImgZYdicW6|dDDoeY1idiCEVES3OEBk\WyuczygTWM2OD13MDDuUS=> Mn7SNVg5ODB5NkO=
Sf9 cells MYHGeY5kfGmxbjDhd5NigQ>? MkXNTY5pcWKrdHnvckBw\iCqdX3hckBz\WOxbXLpcoFvfCCUT1PLNUBmgHC{ZYPz[YQhcW5iU3[5JINmdGy|LDDJR|UxRTBwOEmg{txO M4TYRlE5QDByN{[z
human NCI-H460 cells MWDHdo94fGhiaX7obYJqfGmxbjDhd5NigQ>? MYC3NkBp M3zPcGdzd3e2aDDpcohq[mm2aX;uJI9nKGi3bXHuJG5EUS2KNE[wJINmdGy|IHHmeIVzKDd{IHjyd{BjgSClb4XseIVzKGOxdX70[ZIhdWW2aH;kMEBKSzVyPUWuOEDPxE1? NIT6NHYzPDlyMEi2Ni=>
human PC3 cells NFm3SnhRem:uaX\ldoF1cW:wIHHzd4F6 Mke1O|IhcA>? NXLFSWU4SW62aYDyc4xq\mW{YYTpeoUh[WO2aY\peJkh[WejaX7zeEBpfW2jbjDQR|Mh[2WubIOgZYZ1\XJiN{KgbJJ{KGK7IF3UWEBie3OjeTygTWM2OD1zNT61JO69VQ>? M1XlW|I1OzB6OUm3
HFF cells MWrDfZRwfG:6aXRCpIF{e2G7 MXjDfZRwfG:6aXPpeJkh[WejaX7zeEBJTkZiY3XscJMtKEmFNUC9NVYvOyEQvF2= NUfjWYVXOTh6MEC3OlM>

... Click to View More Cell Line Experimental Data
Assay
Methods Test Index PMID
Western blot
p-Akt / Akt / p-GSK3 / p-mTOR / mTOR / p-p70S6K / p-FoxO3a / p-FoxO1 ; 

PubMed: 20075391     


Western blot analysis of MOVCAR5, MOVCAR6 and SKOV3 cells treated overnight with 10 μM GSK690693. Representative panels were screened with antibodies against components of the Akt signaling cascade to detect diminished phosphorylation of downstream targets.

pPRAS40 / PRAS40 / pBAD / BAD ; 

PubMed: 25551293     


Effect of AKT inhibitors on phosphorylation of AKT and AKT protein substrates. EBC1 cells were treated with the indicated doses of MK2206 and GSK690693 (top), or GDC0068 (bottom) for 24 hr. Treated cells were lysed and analyzed by immunoblot with the indicated antibodies. Phosphorylation of PRAS40, BAD, and GSK3β was quantified by image densitometry (middle). 

20075391 25551293
Growth inhibition assay
Cell viability ; 

PubMed: 20075391     


Murine ovarian carcinoma cells (MOVCAR5 and MOVCAR6) and control human SKOV3 ovarian tumors cells were treated with various concentrations of GSK690693 for 72 hrs and analyzed for cell viability by MTT assays. The IC50 was ~3 μM GSK690693 for MOVCAR5 and SKOV3 cells, whereas, MOVCAR6 cells did not reach an IC50 with the drug concentrations used in this experiment. Error bars depict total standard deviation among replicate samples. 

20075391
In vivo A single administration of GSK690693 inhibits GSK3β phosphorylation in human breast carcinoma (BT474) xenografts in a dose- and time-dependent manner. Similarly, GSK690693 induces a reduction in phosphorylation of the Akt substrates, PRAS40, and FKHR/FKHRL1. GSK690693 also results in an acute increase in blood glucose, returning to baseline 8 to 10 hours after drug administration. Administration of GSK690693 induces reductions in phosphorylated Akt substrates in vivo, and potently inhibits the growth of human SKOV-3 ovarian, LNCaP prostate, and BT474 and HCC-1954 breast carcinoma xenografts, with maximal inhibition of 58% to 75% at the dose of 30 mg/kg/day. [1] GSK690693 exhibits efficacy irrespective of the mechanism of Akt activation involved. GSK690693 is most effective in delaying tumor progression in Lck-MyrAkt2 mice expressing a membrane-bound, constitutively active form of Akt. [3]

Protocol

Kinase Assay:[1]
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In vitro kinase assays:

His-tagged full-length Akt1, 2, or 3 are expressed and purified from baculovirus. Activation is carried out with purified PDK1 to phosphorylate Thr308 and purified MK2 to phosphorylate Ser473. To more accurately measure time-dependent inhibition of Akt, activated Akt enzymes are incubated with GSK690693 at various concentrations at room temperature for 30 minutes before the reaction is initiated with the addition of substrate. Final reaction contains 5 nM to 15 nM Akt1, 2, and 3 enzymes; 2 μM ATP; 0.15 μCi/μL[γ-33P]ATP; 1 μM Peptide (Biotin-aminohexanoicacid-ARKR-ERAYSFGHHA-amide); 10 mM MgCl2; 25 mM MOPS (pH 7.5); 1 mM DTT; 1 mM CHAPS; and 50 mM KCl. The reactions are incubated at room temperature for 45 minutes, followed by termination with Leadseeker beads in PBS containing EDTA (final concentration, 2 mg/mL beads and 75 mM EDTA). The plates are then sealed, the beads are allowed to settle for at least 5 hours, and product formation is quantitated using a Viewlux Imager.
Cell Research:[1]
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  • Cell lines: T47D, ZR-75-1, BT474, HCC1954, MDA-MB-453, LNCaP, etc.
  • Concentrations: Dissolved in DMSO, final concentrations ~30 μM
  • Incubation Time: 72 hours
  • Method: Cells are plated at densities that allow untreated cells to grow logarithmically during the course of a 3-day assay. Briefly, cells are plated in 96- or 384-well plates and incubated overnight. Cells are then treated with GSK690693 (ranging from 30 μM-1.5 nM) and incubated for 72 hours. Cell proliferation is measured using the CellTiter Glo reagent. Data are analyzed using the XLFit curve-fitting tool for Microsoft Excel. IC50 values are obtained by fitting data to Eq, 2.
    (Only for Reference)
Animal Research:[1]
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  • Animal Models: Female CD1 Swiss Nude mice injected with LNCaP, SKOV-3, or PANC1 cells, and C.B-17 SCID mice with HCC1954, MDA-MB-453, or BT474 cells
  • Formulation: Formulated in either 4% DMSO/40% hydroxypropyl-β-cyclodextrin in water (pH 6.0) or 5% dextrose (pH 4.0)
  • Dosages: ~30 mg/kg/day
  • Administration: Administered via i.p.
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 39 mg/mL (91.66 mM)
Water Insoluble
Ethanol Insoluble
In vivo Add solvents to the product individually and in order(Data is from Selleck tests instead of citations):
5% DMSO+30% PEG 300+ddH2O
For best results, use promptly after mixing. 		15mg/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 425.48
Formula

C21H27N7O3
CAS No. 937174-76-0
Storage powder
in solvent
Synonyms N/A

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Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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Frequently Asked Questions

  • Question 1:

    Why pAKT increased after treatment of the inhibitor ?

  • Answer:

    GSK690693 actually inhibits AKT, but not necessarily decrease p-Akt level. Treatment with GSK690693 caused AKT hyper phosphorylation which has already been reported in some papers. (For example, http://www.bloodjournal.org/content/113/8/1723.short?sso-checked=true). To test the inhibition of AKT activity, you might have to look at the level of AKT substrates.

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Akt Signaling Pathway Map

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID