AKT is the central node of PI3K/AKT/mTOR pathway. The PH domain and ATP-competitive site are the main target site for research of new compound[1]. GSK690693 is an ATP-competitive pan AKT inhibitor with IC50 values of 2, 13 and 9nM for AKT 1, 2, and 3, respectively. Treatment with GSK690693 on concentration of 0.01-10uM cause decreased phosphorylation level of GSK3, p70S6K, and PRAS40 in BT474 breast tumor cells in a dose-dependent manner. GSK690693 can induce accumulation of the FOXO3A, an Akt downstream substrate, in the nucleus at concentration >1uM. In growth inhibition studies, cell lines with higher level of p-AKT showed more sensitivity to GSK690693, such as HCC1954, ZR-75-1, BT474 and LNCaP, etc.. In vivo studies showed maximal tumor growth inhibition of 58% to 75% at the end of dosing period with 30mg/kg/day dose of GSK690693 (i.p.) for 21 days in mice bearing established SKOV-3 ovarian, LNCaP prostate, BT474 and HCC-1954 breast carcinoma xenografts[2].
GSK690693 markedly increased the levels of Pim-1 protein but had a minimal effect on the expression of Pim-3 protein and reduced the levels of Pim-2.
Cancer Res. 2013 Jun 1;73(11):3402-11.
PC3-LN4 cells
5 μM
24 h
GSK690693 increased the level of Pim-1 mRNA but not Pim-2 or Pim-3 mRNA.
Cancer Res. 2013 Jun 1;73(11):3402-11.
PC3-LN4 cells
5 μM
24 h
GSK690693 increased the protein levels of multiple RTKs, including MET, EPHA2, RON, EGFR, HER2, HER3, INSR, and IGF1R.
Cancer Res. 2013 Jun 1;73(11):3402-11.
WEHI-231 cells
10 µM
30 min
Inhibition of PI3K signaling pathway
Cells. 2021 Feb 4;10(2):316.
Thymic lymphoma cells
0, 10 or 20 μM
72 h
To evaluate the effect of GSK-690693 on apoptosis, results showed that GSK-690693 induced a 2-3 fold increase in apoptosis within 24 h.
Clin Cancer Res. 2010 Jan 15;16(2):486-96.
MOVCAR5 and MOVCAR6 cells
0, 10 or 20 μM
72 h
To evaluate the effect of GSK-690693 on the cell cycle, results showed that MOVCAR5 cells exhibited ~50% increase in cell cycle arrest in G1 phase.
Clin Cancer Res. 2010 Jan 15;16(2):486-96.
143B cells
10 μM
72 h
GSK690693 attenuated the chemoresistance induced by ZIP10 overexpression
J Exp Clin Cancer Res. 2021 Oct 27;40(1):340.
SW1990
1-10 µM
72 h
GSK690693 significantly alleviated the adenosine-induced p21 upregulation and augmented Akt phosphorylation via a negative feedback loop.
EBioMedicine. 2019 Sep;47:114-127.
BxPC-3
1-10 µM
72 h
GSK690693 significantly alleviated the adenosine-induced p21 upregulation and augmented Akt phosphorylation via a negative feedback loop.
EBioMedicine. 2019 Sep;47:114-127.
143B cells
10 μM
72 h
GSK690693 attenuated the chemoresistance induced by ZIP10 overexpression.
J Exp Clin Cancer Res. 2021 Oct 27;40(1):340.
A549 cells
5.93 µM
24 h
Evaluate the Akt inhibitory effect of GSK-690693 on A549 cells, showing an IC50 value of 5.93 µM.
Int J Mol Sci. 2023 Jan 31;24(3):2648.
Thymic lymphoma cells
10 μM
8 h
To detect the inhibitory effect of GSK690693 on phosphorylation of downstream targets of the Akt signaling pathway
Clin Cancer Res. 2010 Jan 15;16(2):486-96.
Ovarian cancer cells
10 μM
Overnight
To detect the inhibitory effect of GSK690693 on phosphorylation of downstream targets of the Akt signaling pathway
Clin Cancer Res. 2010 Jan 15;16(2):486-96.
GSK-690693 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
AOM/DSS-induced CAC model
Intraperitoneal injection
30 mg/kg
Three times a week for two weeks
GSK-690693 inhibited the promoting effect of 5-HT on tumor growth
Theranostics. 2022 May 9;12(8):3928-3945
Nude mice
PC3-LN4 xenograft model
Intraperitoneal injection
30 mg/kg
Daily for 21 days
GSK690693 alone caused a modest inhibition of tumor growth, but the combined treatment with the Pim inhibitor SMI-4a resulted in a markedly greater inhibition of tumor growth.
To evaluate the effect of GSK-690693 on tumor development, results showed that GSK-690693 delayed tumor development and reduced tumor size in various mouse models.
Clin Cancer Res. 2010 Jan 15;16(2):486-96.
Mice
KrasG12D-driven skin cancer model
Intraperitoneal injection
30 mg/kg
Daily for 10 days
GSK690693 had only a small effect on SCC tumor regression, even at a dose that markedly reduced Akt signaling activity.
Cancer Res. 2012 Nov 15;72(22):5966-75
Nude mice
143B cell xenograft model
Intraperitoneal injection
30 mg/kg
Once daily for 30 days
GSK690693 attenuated the tumor growth and chemoresistance induced by ZIP10 overexpression
J Exp Clin Cancer Res. 2021 Oct 27;40(1):340.
Mice
Orthotopic pancreatic cancer model
Intraperitoneal injection
20 mg/kg
Every other day for 6 weeks
GSK690693 further enhanced the therapeutic effect of adenosine on pancreatic cancer, reducing tumor volume and increasing caspase-3 activation.
EBioMedicine. 2019 Sep;47:114-127.
Nude mice
Xenograft tumor model
Intraperitoneal injection
30 mg/kg
Once daily for 30 days
GSK690693 attenuated the tumor growth and chemoresistance induced by ZIP10 overexpression.
J Exp Clin Cancer Res. 2021 Oct 27;40(1):340.
Mice
Lck-MyrAkt2 transgenic mice
Intraperitoneal injection
30 mg/kg
Once daily, 5 days per week, for 4 weeks
To evaluate the efficacy of GSK690693 in delaying tumor development and reducing tumor size
United States, Indiana
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United States, Indiana
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GSK Investigational Site
Indianapolis, Indiana, United States, 46202
United States, Michigan
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