Home PI3K/Akt/mTOR Akt inhibitor - PKA inhibitor - PKC inhibitor - AMPK inhibitor - Autophagy inhibitor - STING inhibitor - ULK inhibitor - DAPK inhibitor GSK690693 For research use only.

GSK690693

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. GSK690693 also potently inhibits AMPK and DAPK3 from the CAMK family with IC50 of 50 nM and 81 nM, respectively. GSK690693 affects Unc-51-like autophagy activating kinase 1 (ULK1) activity, robustly inhibits STING-dependent IRF3 activation. Phase 1.

GSK690693 Chemical Structure

GSK690693 Chemical Structure

CAS No. 937174-76-0

Purity & Quality Control

GSK690693 Related Products

Signaling Pathway

Akt Signaling Pathways

Akt Signaling Pathway

Cell Data

Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
LNCaP Proliferation assay Antiproliferative activity against human LNCaP cells, IC50=20 nM 18800763
BT474 Proliferation assay Antiproliferative activity against human BT474 cells, IC50=50 nM 18800763
Sf9 Function assay Inhibition of human recombinant ROCK1 expressed in Sf9 cells, IC50=0.89 μM 18800763
NCI-H460 Growth inhibition assay 72 h Growth inhibition of human NCI-H460 cells after 72 hrs by coulter counter method, IC50=5.4 μM 24900862
PC3 Proliferation assay 72 h Antiproliferative activity against human PC3 cells after 72 hrs by MTT assay, IC50=15.5 μM 24308997
HFF Cytotoxic assay Cytotoxicity against HFF cells, IC50=16.3 μM 18800763
LNCAP Antiproliferative assay Antiproliferative activity against human LNCAP cells, IC50 = 0.021 μM. 19179070
BT474 Antiproliferative assay Antiproliferative activity against human BT474 cells, IC50 = 0.069 μM. 19179070
BT474 Function assay Inhibition of GSK3-beta phosphorylation in human BT474 cells, IC50 = 0.138 μM. 19179070
JVM2 Antiproliferative assay 72 hrs Antiproliferative activity against human JVM2 cells after 72 hrs by CellTiter Glo assay, IC50 = 1.6 μM. 28704757
JeKo1 Antiproliferative assay 72 hrs Antiproliferative activity against human JeKo1 cells after 72 hrs by CellTiter Glo assay, IC50 = 3 μM. 28704757
Z138 Antiproliferative assay 72 hrs Antiproliferative activity against human Z138 cells after 72 hrs by CellTiter Glo assay, IC50 = 3.1 μM. 28704757
SP49 Antiproliferative assay 72 hrs Antiproliferative activity against human SP49 cells after 72 hrs by CellTiter Glo assay, IC50 = 4.8 μM. 28704757
Maver1 Antiproliferative assay 72 hrs Antiproliferative activity against human Maver1 cells after 72 hrs by CellTiter Glo assay, IC50 = 5.1 μM. 28704757
C6 Function assay 24 hrs Inhibition of Akt in rat C6 cells after 24 hrs by ELISA, IC50 = 6.97 μM. 29966916
C6 Cytotoxicity assay 24 hrs Cytotoxicity against rat C6 cells assessed as decrease in cell viability after 24 hrs by MTT assay, IC50 = 14.5 μM. 29966916
A549 Function assay 24 hrs Inhibition of Akt in human A549 cells after 24 hrs by ELISA, IC50 = 17.33 μM. 29966916
Mino Antiproliferative assay 72 hrs Antiproliferative activity against human Mino cells after 72 hrs by CellTiter Glo assay, IC50 = 20.8 μM. 28704757
A673 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for A673 cells 29435139
RD qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for RD cells 29435139
NB1643 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for NB1643 cells 29435139
SJ-GBM2 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SJ-GBM2 cells 29435139
SK-N-MC qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SK-N-MC cells 29435139
NB-EBc1 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for NB-EBc1 cells 29435139
LAN-5 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for LAN-5 cells 29435139
MCL Antiproliferative assay 24 hrs Antiproliferative activity against primary human MCL cells up to 60 uM after 24 hrs by CellTiter Glo assay 28704757
Click to View More Cell Line Experimental Data

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. GSK690693 also potently inhibits AMPK and DAPK3 from the CAMK family with IC50 of 50 nM and 81 nM, respectively. GSK690693 affects Unc-51-like autophagy activating kinase 1 (ULK1) activity, robustly inhibits STING-dependent IRF3 activation. Phase 1.
Targets
ULK1 [4] STING [4] AMPK [4] Akt1 [1]
(Cell-free assay)		 PKCη [1]
(Cell-free assay)		 Click to View More Targets
2 nM 2 nM
In vitro
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]
Kinase Assay 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 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.
Experimental Result Images Methods Biomarkers Images PMID
Western blot pPRAS40 / PRAS40 / pBAD / BAD p-Akt / Akt / p-GSK3 / p-mTOR / mTOR / p-p70S6K / p-FoxO3a / p-FoxO1 25551293
Growth inhibition assay Cell viability 20075391
In Vivo
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]
Animal Research 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
Dosages ~30 mg/kg/day
Administration Administered via i.p.
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

Chemical Information & Solubility

Molecular Weight 425.48 Formula

C21H27N7O3
CAS No. 937174-76-0 SDF Download GSK690693 SDF
Smiles CCN1C2=C(C(=NC=C2OCC3CCCNC3)C#CC(C)(C)O)N=C1C4=NON=C4N
Storage (From the date of receipt)

In vitro
Batch:

DMSO : 21 mg/mL ( (49.35 mM) Moisture-absorbing DMSO reduces solubility. Please use fresh DMSO.)

Water : Insoluble

Ethanol : Insoluble


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In vivo
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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.

Handling Instructions

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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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