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Purity: ≥98%
GSK690693, an aminofurazan derivative, is a novel, potent and ATP-competitive pan-Akt inhibitor targeting Akt1/2/3 with potential anticancer activity. With IC50 values of 2 nM, 13 nM, and 9 nM in cell-free assays, it inhibits Akt1/2/3. GSK690693's antiproliferative effects were specific to cancer cells because it had no effect on the growth of healthy mouse thymocytes or normal human CD4(+) peripheral T lymphocytes. GSK690693 treatment decreased the phosphorylation of downstream AKT substrates in both sensitive and insensitive cell lines, indicating that the lack of AKT kinase inhibition was not the root cause of resistance.
| Targets |
Akt1 (IC50 = 2 nM); Akt3 (IC50 = 9 nM); Akt2 (IC50 = 13 nM); PKCη (IC50 = 2 nM); PKCθ (IC50 = 2 nM); PrkX (IC50 = 5 nM); PAK6 (IC50 = 6 nM); PAK4 (IC50 = 10 nM); PKCδ (IC50 = 14 nM); PKCβ1 (IC50 = 19 nM); PKCε (IC50 = 21 nM); PKA (IC50 = 24 nM); PKG1β (IC50 = 33 nM); AMPK (IC50 = 50 nM); PAK5 (IC50 = 52 nM); DAPK3 (IC50 = 81 nM); Autophagy
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| ln Vitro |
GSK690693 is very selective for the Akt isoforms versus the majority of kinases in other families. With IC50 values of 24 nM, 5 nM, and 2-21 nM, respectively, GSK690693 is less selective for AGC kinase family members such as PKA, PrkX, and PKC isozymes. Additionally, PAK4, 5, and 6 from the STE family have IC50 values of 10 nM, 52 nM, and 6 nM, respectively. GSK690693 also potently inhibits AMPK and DAPK3 from the CAMK family. With an IC50 ranging from 43 nM to 150 nM, GSK690693 prevents tumor cells from phosphorylating GSK3. The nuclear accumulation of the transcription factor FOXO3A is increased dose-dependently by treatment with GSK690693. The IC50 values for GSK690693 are as follows: 72 nM, 79 nM, 86 nM, 119 nM, 975 nM, and 147 nM for T47D, ZR-75-1, BT474, HCC1954, MDA-MB-453, and LNCaP cells, respectively. In both LNCaP and BT474 cells, treatment with GSK690693 induces apoptosis at concentrations >100 nM. [1] GSK690693 induces apoptosis in susceptible ALL cell lines, supporting the function of AKT in cell survival.[2]
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| ln Vivo |
GSK690693 inhibits GSK3 phosphorylation in human breast carcinoma (BT474) xenografts in a dose- and time-dependent manner after a single administration. The Akt substrates PRAS40 and FKHR/FKHRL1 are reduced in phosphorylation when GSK690693 is administered. Blood glucose levels are also acutely elevated by GSK690693 but return to normal 8 to 10 hours later. The growth of human SKOV-3 ovarian, LNCaP prostate, and BT474 and HCC-1954 breast carcinoma xenografts is potently inhibited by the administration of GSK690693, with a maximal inhibition of 58% to 75% at the dose of 30 mg/kg/day.[1] GSK690693 is effective regardless of the Akt activation mechanism at play. When administered to Lck-MyrAkt2 mice, which express a membrane-bound, constitutively active form of Akt, GSK690693 slows the progression of tumors the best. [3]
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| Enzyme Assay |
Expressed and purified from baculovirus is full-length Akt1, 2, or 3 that has been His-tagged. Purified PDK1 and MK2, which phosphorylate Ser473 and Thr308, respectively, are used to activate the protein. Activated Akt enzymes are incubated with GSK690693 at varying concentrations at room temperature for 30 minutes prior to the addition of substrate to start the reaction in order to more precisely measure time-dependent inhibition of Akt. 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 allowed to sit for 45 minutes at room temperature before being stopped with Leadseeker beads in PBS containing EDTA (2 mg/mL beads at a final concentration of 75 mM EDTA). The plates are next sealed, the beads are given at least 5 hours to settle, and a Viewlux Imager is used to quantify product formation.
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| Cell Assay |
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.
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| Animal Protocol |
In 8–12-week-old CD1 Swiss Nude mice (LNCaP, SKOV-3, and PANC1) or SCID mice (HCC1954, MDA-MB-453, and BT474), tumors are induced by subcutaneous injection of tumor cell suspension (HCC1954, MDA-MB-453, and LNCaP) or tumor fragments (BT474, SKOV-3, and PANC1) or tumor fragments. A randomization procedure is used to divide the mice into groups of 8–12 mice each once tumors reach a volume of 100–200 mm3. A dose of 10, 20, or 30 mg/kg of GSK690693 is given intravenously once daily. At the end of the experiment, animals are put to death by CO2 inhalation. Using calipers and the formula tumor volume (mm3)=(length width2)/2, tumor volume is calculated twice per week. Results are presented as% inhibition on day 21 of treatment=100 [1-(average growth of the drug-treated population/average growth of the vehicle-treated control population)]. The two-tailed t test is used for statistical analysis.
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| References |
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| Additional Infomation |
GSK690693 is a member of the class of imidazopyridines that is 4-(1-ethylimidazo[4,5-c]pyridin-4-yl)-2-methylbut-3-yn-2-ol carrying additional 2-(4-amino-1,2,5-oxadiazol-3-yl and [(3S)-piperidin-3-yl]methoxy substituents at positions 4 and 7 respectively. It has a role as an EC 2.7.11.1 (non-specific serine/threonine protein kinase) inhibitor and an antineoplastic agent. It is an imidazopyridine, a member of piperidines, a 1,2,5-oxadiazole, an aromatic ether, a tertiary alcohol, an acetylenic compound, an aromatic amine and a primary amino compound.
GSK690693 has been used in trials studying the treatment of Tumor, CANCER, and Lymphoma. Pan-AKT Kinase Inhibitor GSK690693 is an aminofurazan-derived inhibitor of Akt kinases with potential antineoplastic activity. Pan-AKT kinase inhibitor GSK-690693 binds to and inhibits Akt kinases 1, 2, and 3, which may result in the inhibition of protein phosphorylation events downstream from Akt kinases in the PI3K/Akt signaling pathway, and, subsequently, the inhibition of tumor cell proliferation and the induction of tumor cell apoptosis. In addition, this agent may inhibit other protein kinases including protein kinase C (PKC) and protein kinase A (PKA). As serine/threonine protein kinases which are involved in a number of biological processes, AKT kinases promote cell survival by inhibiting apoptosis and are required for glucose transport. |
| Molecular Formula |
C21H27N7O3
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|---|---|
| Molecular Weight |
425.4842
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| Exact Mass |
425.217
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| Elemental Analysis |
C, 59.28; H, 6.40; N, 23.04; O, 11.28
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| CAS # |
937174-76-0
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| Related CAS # |
AKT Kinase Inhibitor;842148-40-7
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| PubChem CID |
16725726
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| Appearance |
Light yellow to yellow solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
683.8±65.0 °C at 760 mmHg
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| Flash Point |
367.3±34.3 °C
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| Vapour Pressure |
0.0±2.2 mmHg at 25°C
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| Index of Refraction |
1.683
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| LogP |
4.34
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
31
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| Complexity |
680
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C(N1C(C2=NON=C2N)=NC2C(=NC=C(C1=2)OC[C@@H]1CNCCC1)C#CC(O)(C)C)C
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| InChi Key |
KGPGFQWBCSZGEL-ZDUSSCGKSA-N
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| InChi Code |
InChI=1S/C21H27N7O3/c1-4-28-18-15(30-12-13-6-5-9-23-10-13)11-24-14(7-8-21(2,3)29)16(18)25-20(28)17-19(22)27-31-26-17/h11,13,23,29H,4-6,9-10,12H2,1-3H3,(H2,22,27)/t13-/m0/s1
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| Chemical Name |
4-[2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-[[(3S)-piperidin-3-yl]methoxy]imidazo[4,5-c]pyridin-4-yl]-2-methylbut-3-yn-2-ol
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| Synonyms |
GSK690693; GSK 690693; GSK-690693
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: ~39 mg/mL (~91.7 mM)
Water: <1 mg/mL Ethanol: <1 mg/mL |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.88 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 2: 2 mg/mL (4.70 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. View More
Solubility in Formulation 3: 2 mg/mL (4.70 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. Solubility in Formulation 4: 15% Captisol: 30mg/mL Solubility in Formulation 5: 10 mg/mL (23.50 mM) in 20% HP-β-CD/10 mM citrate pH 2.0 (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3503 mL | 11.7514 mL | 23.5029 mL | |
| 5 mM | 0.4701 mL | 2.3503 mL | 4.7006 mL | |
| 10 mM | 0.2350 mL | 1.1751 mL | 2.3503 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT00666081 | Withdrawn | Drug: GSK690693 | Cancer | GlaxoSmithKline | April 2008 | Phase 1 |
| NCT00493818 | Terminated | Drug: GSK690693 | Cancer | GlaxoSmithKline | April 2007 | Phase 1 |
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