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| 5mg |
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| 25mg |
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Purity: ≥98%
GSK2334470 (GSK-2334470) is a novel, highly specific and potent inhibitor of PDK1 (3-phosphoinositide-dependent protein kinase) with potential antitumor activity.In a cell-free assay, it inhibits PDK-1 with an IC50 of 10 nM and has no impact on closely related AGC-kinases. GSK2334470 inhibited PDK1 from activating full-length Akt1 or mutant Akt1 lacking the PH domain, which resulted in strong antiproliferative activity in vitro and high antitumor efficacy in vivo.
| Targets |
PDK1 (IC50 = 10 nM)
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|---|---|
| ln Vitro |
GSK2334470 inhibits PDK1 from activating full-length Akt1 in the presence of PtdIns(3,4,5)P3-containing lipid vesicles or a mutant of Akt1 lacking the PH domain (ΔPH-Akt1) with IC50 of ~10 nM. With an IC50 of less than 10 nM, GSK2334470 similarly prevents PDK1 from phosphorylating the PDKtide peptide substrate. In HEK-293 cells, GSK2334470 (0.1 M-0.3 M) causes a significant dose-dependent inhibition of endogenous NDRG1 with a phosphorylation reduction of over 50%. In HEK-293 cells, GSK2334470 (30 nM) causes a significant, dose-dependent inhibition of each SGK isoform's T-loop phosphorylation. GSK2334470 (30 µM) suppresses U46619 induced Ca2+-sensitized force in α-toxin permeabilized rabbit pulmonary artery SM. GSK2334470 (30 µM) results in a significant decrease in the contractile force in response to [Ca2+]. [2]GSK2334470 (1 μM) results in total abrogation of the EGF-induced intracellular calcium increase and inositol phosphates accumulation in MDA-MB-231 cells. GSK2334470 (1 μM) inhibits PLCγ1 Tyr783 phosphorylation in MDA-MB-231 cells. [3]
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| ln Vivo |
GSK2334470 is a highly specific and potent PDK1 inhibitor.
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| Enzyme Assay |
Endogenous Akt, S6K, and RSK are immunoprecipitated using 3 g to 5 g of the designated antibodies from 0.1 mg to 1 mg of cell lysate for two hours at 4 °C on a vibrating platform. In order to measure the SGK activity, 150 g of transfected lysate is incubated with 5 g of glutathione-Sepharose at 4 °C for 3 hours. The immunoprecipitates are then washed twice with kinase buffer and twice with lysis buffer containing 0.5 mM NaCl. A reaction mixture is used to start kinase reactions, resulting in final concentrations of 0.1 mM [-32P]ATP (200 c.p.m./pmol), 5 mM magnesium acetate, 0.1% 2-mercaptoethanol, and 30 mM Crosstide peptide (GRPRTSSFAEGKK).
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| Cell Assay |
GSK2334470 is dissolved in DMSO and diluted with appropriate medium before use. GSK2334470 is administered to non-resistant cells and resistant sublines for 1.5 and 12 hours in 10% FBS medium with/without MK-2206 (5 M) to investigate its inhibitory effect on the mTOR-S6K pathway.
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| Animal Protocol |
In order to dilute the mice, DMSO is first dissolved in PBS or saline. As previously mentioned, BrafV600E::Pten are generated. Each experimental group utilizes cohorts of six animals. Based on previous studies[3], GSK2334470 is administered by IP injection (100 mg/kg) three times per week beginning on the day that 4-hydroxytamoxifen is topically applied and ending at the time of mouse collection.
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| References | |
| Additional Infomation |
(3S,6R)-1-[6-(3-amino-1H-indazol-6-yl)-2-(methylamino)-4-pyrimidinyl]-N-cyclohexyl-6-methyl-3-piperidinecarboxamide is a member of indazoles.
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| Molecular Formula |
C25H34N8O
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|---|---|---|
| Molecular Weight |
462.5905
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| Exact Mass |
462.285
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| Elemental Analysis |
C, 64.91; H, 7.41; N, 24.22; O, 3.46
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| CAS # |
1227911-45-6
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| Related CAS # |
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| PubChem CID |
46215815
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| Appearance |
white solid powder
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| Density |
1.3±0.1 g/cm3
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| Index of Refraction |
1.667
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| LogP |
2.31
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
34
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| Complexity |
688
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| Defined Atom Stereocenter Count |
2
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| SMILES |
O=C([C@]1([H])C([H])([H])N(C2C([H])=C(C3C([H])=C([H])C4C(N([H])[H])=NN([H])C=4C=3[H])N=C(N([H])C([H])([H])[H])N=2)[C@]([H])(C([H])([H])[H])C([H])([H])C1([H])[H])N([H])C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H]
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| InChi Key |
QLPHOXTXAKOFMU-WBVHZDCISA-N
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| InChi Code |
InChI=1S/C25H34N8O/c1-15-8-9-17(24(34)28-18-6-4-3-5-7-18)14-33(15)22-13-20(29-25(27-2)30-22)16-10-11-19-21(12-16)31-32-23(19)26/h10-13,15,17-18H,3-9,14H2,1-2H3,(H,28,34)(H3,26,31,32)(H,27,29,30)/t15-,17+/m1/s1
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| Chemical Name |
(3S,6R)-1-(6-(3-amino-1H-indazol-6-yl)-2-(methylamino)pyrimidin-4-yl)-N-cyclohexyl-6-methylpiperidine-3-carboxamide
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| Synonyms |
GSK 2334470; GSK2334470; GSK-2334470
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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 |
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| 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: ~90 mg/mL (194.6 mM)
Water: <1 mg/mL Ethanol: 90 mg/mL (194.6 mM) |
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.40 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (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 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. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.40 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (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 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (5.40 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1617 mL | 10.8087 mL | 21.6174 mL | |
| 5 mM | 0.4323 mL | 2.1617 mL | 4.3235 mL | |
| 10 mM | 0.2162 mL | 1.0809 mL | 2.1617 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.
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