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.

Size Price Stock Quantity  
In DMSO USD 221 In stock
USD 170 In stock
USD 770 In stock
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5 Customer Reviews

  • UPN cells were treated with GSK690693 or MK2206 (1 uM) for 1h followed by LPA (10 uM), EGF or IGF-1 (10 ng/ml) for another 1h and Western blot was performed. Band intensities of phospho-AKT (p-AKTS473), phospho-S6 (p-S6S240/S244), phospho-YB-1 (p-YB-1S102) and YB-1 were quantified and normalized to the intensity of ERK2. It directly determined the role of AKT using two potent, AKT inhibitors with distinct actions—a catalytic domain inhibitor, GSK690693, and an allosteric inhibitor, MK2206 -in UPN and SKOV3 cells, which showed appreciable AKT and YB-1 phosphorylation upon growth factor stimulation. GSK690693 increased basal and growth factor-induced AKT phosphorylation due to blocking a negative feedback loop downstream of AKT, whereas MK2206 abolished both basal and growth-factor-induced AKT phosphorylation.
     
     

    Oncogene 2014 33(22), 2846-56. GSK690693 purchased from Selleck.

    Western blotting demonstrated that ART3 expression did not exhibit a significant change in MDA-MB-231 cells treated either p-AKT inhibitor (GSK690693) or p-ERK inhibitor (AZD6244).

    Oncotarget, 2016, 7(29):46589-46602. GSK690693 purchased from Selleck.

  • IKBKE-transfected or insulin-simulated H1299 cells were treated with indicated Akt inhibitors (e.g. perifosine 5 uM, MK2206 10 uM, and GSK690693 10 uM), following transfection of PDK1-null and parental HCT116 cells with HA-Akt, wild-type and constitutively active IKBKE, Western blot analysis was performed.

    J Biol Chem 2011 286(43), 37389-98. GSK690693 purchased from Selleck.

    Cell growth of sensitive (DLD1 and U87) and multi-drug resistant (DLD1-TxR and U87-TxR) cells assessed after 72 h of GSK690693 treatment. GSK690693 efficacy decreased in DLD1-TxR in comparison to its sensitive counterpart - DLD1. Colorectal carcinoma cell line (DLD1) possesses mutated p53, while its resistant counterpart (DLD1-TxR) additionally acquired the LOH in PTEN gene during the course of resistance induction. However, concentration-dependent cell growth inhibition induced by GSK690693 does not differ between sensitive (U87) and resistant (U87-TxR) glioblastoma cell lines. Both, U87 and U87-TxR have wt-p53 and PTEN-null. The results were obtained by the Sulforhodamine B assay. All values represent average ±SD obtained from two independent experiments, n = 5.

    Dr. Milica Pesic of Institute for Biological Research. GSK690693 purchased from Selleck.

  • The effects of SelleckChem inhibitors on sea urchin embryo development evaluated 24 h after fertilization. All compounds were added to embryos suspension 20 min after fertilization. The relative presence of late gastrula, swimming blastula, undeveloped embryos and dead embryos was compared next to untreated control embryos (A). Fertilized egg, swimming blastula and late gastrula are illustrated (B). The embryonic development was relatively synchronized in untreated control samples after 24 h (A, E). GSK690693 treatment sustained the development of embryos. Swimming blastulas kept normal motility regardless the deformities in their shape. Tipifarnib treatment induced significant toxicity due to occurrence of dead fragmented embryos. Some abnormal blastulas kept the motility. AZD2014 treatment sustained the development of embryos. Some developed gastrulas and blastulas were less motile in comparison with control (A, C). WZ811 was the least toxic compound. Significant number of gastrulas and blastulas was developed. However, their motility was considerably suppressed (A, D). In contrast to SelleckChem inhibitors, classic anticancer agent-cisplatin was extremely toxic to sea urchin embryos (A). Cisplatin killed many embryos, while a small amount of survived embryos was stopped at early phases of development: immediately after fertilization or after first and second division (A, F).

    Dr. Milica Pesic from Institute for Biological Research. GSK690693 purchased from Selleck.

Purity & Quality Control

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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 MmHZVJJwdGmoZYLheIlwdiCjc4PhfS=> Mn;IRY51cXC{b3zp[oVz[XSrdnWgZYN1cX[rdImgZYdicW6|dDDoeY1idiCOTlPhVEBk\WyuczygTWM2OD1{MDDuUS=> Ml7NNVg5ODB5NkO=
human BT474 cells M4LNS3Bzd2yrZnXyZZRqd25iYYPzZZk> NFW4fpZCdnSrcILvcIln\XKjdHn2[UBi[3Srdnn0fUBi\2GrboP0JIh2dWGwIFLUOFc1KGOnbHzzMEBKSzVyPUWwJI5O MV6xPFgxODd4Mx?=
Sf9 cells NF\KXWtHfW6ldHnvckBie3OjeR?= NGDhTYtKdmirYnn0bY9vKG:oIHj1cYFvKHKnY3;tZolv[W62IGLPR2syKGW6cILld5Nm\CCrbjDT[lkh[2WubIOsJGlEPTB;MD64PUDPxE1? NHvseWUyQDhyMEe2Ny=>
human NCI-H460 cells MlXkS5Jwf3SqIHnubIljcXSrb36gZZN{[Xl? MXu3NkBp NFHObnZIem:5dHigbY5pcWKrdHnvckBw\iCqdX3hckBPS0lvSES2NEBk\WyuczDh[pRmeiB5MjDodpMh[nliY3;1cJRmeiClb4XueIVzKG2ndHjv[EwhUUN3ME21MlQh|ryP M322U|I1QTByOE[y
human PC3 cells NGPWfI5Rem:uaX\ldoF1cW:wIHHzd4F6 MYG3NkBp MYrBcpRqeHKxbHnm[ZJifGm4ZTDhZ5Rqfmm2eTDh[4FqdnO2IHj1cYFvKFCFMzDj[YxteyCjZoTldkA4OiCqcoOgZpkhVVSWIHHzd4F6NCCLQ{WwQVE2NjVizszN NWH2e3JbOjR|MEi5PVc>
HFF cells M{PDNGN6fG:2b4jpZ:Kh[XO|YYm= M2TOUWN6fG:2b4jpZ4l1gSCjZ3HpcpN1KEiIRjDj[YxteyxiSVO1NF0yPi5|IN88US=> NInJVW4yQDhyMEe2Ny=>

... Click to View More Cell Line Experimental Data

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]
+ Expand
  • 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 individually and in order:
5% DMSO+30% PEG 300+ddH2O
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
Synonyms N/A

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Clinical Trial Information

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT00666081 Withdrawn Cancer GlaxoSmithKline April 2008 Phase 1
NCT00493818 Terminated Cancer GlaxoSmithKline April 2007 Phase 1

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.

Handling Instructions

Tel: +1-832-582-8158 Ext:3

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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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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID