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GSK690693

Cat. No. M1789
GSK690693 Structure
Synonym:

GSK-690693

Size Price Availability Quantity
10mg USD 100 In stock
50mg USD 380 In stock
100mg USD 600 In stock
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Quality Control
Biological Activity

GSK690693 is a small molecule ATP-competitive inhibitor of the pro-survival kinase Akt. Since Akt regulates multiple downstream targets including transcription factors, glycogen synthase 3, the pro-apoptotic protein Bad, as well as MDM2 and mTORC1, it was tested against the in vitro and in vivo panels of the Pediatric Preclinical Testing Program (PPTP). Intraperitoneal administration of GSK690693 in uncompromised mice resulted in the inhibition of GSK3b and repeated dosing of 25 in BT474 breast carcinoma xenograft mice produced a significant delay in tumor growth. GSK690693 inhibited cell growth in vitro with IC(50) values between 6.5 nM and >10µM. In vivo, GSK690693 significantly increased EFS in 11 of 34 (32%) solid tumor xenografts, most notably in all 6 osteosarcoma models, but not in any of the 8 ALL xenografts tested. No objective responses were observed and only one solid tumor met EFS T/C criteria for intermediate activity.

Protocol
Cell Experiment
Cell lines 786-O, H157, MDA-MB-468, and PC-3, LNCaP and BT474 cells
Preparation method Proliferation assay.
Cell proliferation assays were performed for a number of cell lines as described earlier with some modifications. For these assays, cells were plated at densities that allowed untreated cells to grow logarithmically during the course of a 3-d assay. Briefly, cells were plated in 96- or 384-well plates in culture medium containing 10% fetal bovine serum and incubated overnight at 37° C in 5% CO2. Cells were then treated with GSK690693 (ranging from 30 μmol/L-1.5 nmol/L) and incubated for 72 h. Cell proliferation was measured using the CellTiter Glo (Promega) reagent according to the manufacturer's protocol. Data were analyzed using the XLFit (IDBS Ltd.) curve-fitting tool for Microsoft Excel. IC50 values were obtained by fitting data to Eq. 2.
Concentrations 1.5nM~30 μ M
Incubation time 3 days
Animal Experiment
Animal models Mice bearing established human tumor xenografts (BT-474, HCC-1954, Lncap, SKOV3)
Formulation formulated in either 4% DMSO/40% hydroxypropyl-β-cyclodextrin in water (pH 6.0) or 5% dextrose (pH 4.0)
Dosages once daily at 10, 20, and 30 mg/kg for 21 days
Administration i.p.
Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)
Species Mouse Rat Rabbit Guinea pig Hamster Dog
Weight (kg) 0.02 0.15 1.8 0.4 0.08 10
Body Surface Area (m2) 0.007 0.025 0.15 0.05 0.02 0.5
Km factor 3 6 12 8 5 20
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Chemical Information
Molecular Weight 425.48
Formula C21H27N7O3
CAS Number 937174-76-0
Purity 100.00%
Solubility DMSO
Storage at -20°C
References

Initial testing (stage 1) of the Akt inhibitor GSK690693 by the pediatric preclinical testing program.
Carol H, et al. Pediatr Blood Cancer. 2010 Dec 15;55(7):1329-37. PMID: 20740623.

Causal reasoning identifies mechanisms of sensitivity for a novel AKT kinase inhibitor, GSK690693.
Kumar R, et al. BMC Genomics. 2010 Jul 6;11:419. PMID: 20604938.

GSK690693 delays tumor onset and progression in genetically defined mouse models expressing activated Akt.
Altomare DA, et al. Clin Cancer Res. 2010 Jan 15;16(2):486-96. PMID: 20075391.

AKT inhibitor, GSK690693, induces growth inhibition and apoptosis in acute lymphoblastic leukemia cell lines.
Levy DS, et al. Blood. 2009 Feb 19;113(8):1723-9. PMID: 19064730.

Identification of 4-(2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(3S)-3-piperidinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol (GSK690693), a novel inhibitor of AKT kinase.
Heerding DA, et al. J Med Chem. 2008 Sep 25;51(18):5663-79. PMID: 18800763.

Characterization of an Akt kinase inhibitor with potent pharmacodynamic and antitumor activity.
Rhodes N, et al. Cancer Res. 2008 Apr 1;68(7):2366-74. PMID: 18381444.

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  Catalog
Abmole Inhibitor Catalog 2017




Keywords: GSK690693, GSK-690693 supplier, Akt, inhibitors

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