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Purity: ≥98%
In vitro, Compound 401 targets mTOR but not PI3K and is a potent synthetic inhibitor of DNA-dependent protein kinase (IC50 = 0.28 M for DNA-PK). To test the cellular impact of mTOR inhibition without confounding side effects on PI3K, compound 401 was employed. When cells were treated with 401, the phosphorylation of the Akt Ser(473) and ribosomal protein S6 kinase 1 Thr(389) sites that were altered by the mTOR-Rictor and mTOR-Rictor complexes was prevented. In contrast, Akt Thr(308) phosphorylation, which is reliant on PI3K, was not directly inhibited. In cells lacking DNA-PK, comparable results were also seen. TSC1+/+ cells were resistant to 401, but it inhibited the proliferation of TSC1-/- fibroblasts. Long-term treatment with 401 did not increase the level of phosphorylated Akt Ser(473), in contrast to rapamycin, in TSC1-/- cells. The fact that the level of apoptosis increased in the presence of 401 but not rapamycin may be due to the fact that increased Akt activity encourages survival. These findings imply that mTOR kinase inhibitors may be more efficient than rapamycins in preventing the development of TSC hamartomas and other tumors that depend on increased mTOR activity. Numerous human tumors, such as hamartomas connected to tuberous sclerosis complex (TSC), have hyperactive mTOR signaling. LY294002 is one of many small molecules that inhibits mTOR kinase activity while also inhibiting phosphatidylinositol 3-kinase (PI3K) at comparable concentrations.
| Targets |
DNA-PK (IC50 = 0.28 μM); mTOR (IC50 = 5.3 μM)
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| ln Vitro |
Compound 401 is a potent inhibitor of DNA-PK (IC50=0.28 μM). Compound 401 reportedly performs poorly in vitro as an inhibitor of PI3K, ATM, and ATR but is effective against mTOR. mTOR is active against compound 401 (IC50=5.3 μM), but p110/p85 PI3K is not (IC50>100 μM). When cells are exposed to Compound 401, these sites—ribosomal protein S6 kinase 1 Thr389 and Akt Ser473—that have been altered by the mTOR-Rictor and mTOR-Raptor complexes are no longer phosphorylated. However, Akt Thr308 phosphorylation, which is PI3K-dependent, is not directly inhibited. Cells lacking DNA-PK show a similar pattern of behavior. Compound 401 inhibits endogenous or immunoprecipitated epitope-tagged mTOR in Raptor immunoprecipitates. At 5 μM or 10 μM, respectively, of compound 401, inhibition of 67% or 78% is obtained in both cases. Contrarily, dose response curves reveal that Compound 401 exhibits only modest inhibition of the p110α/p85α or p110β/p85α PI3K complexes at these concentrations. TSC1+/+ cells are resistant to Compound 401's proliferative inhibitory effects on TSC1-/- fibroblasts[1].
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| Enzyme Assay |
FreeStyle 293-F cells are transfected with cDNA for AU1-mTOR using 293fectin. The cells are lysed two days later, and mTOR immunoprecipitates are made using AU1 antibody. Raptor antibody can also be used to immunoprecipitate the mTORC1 complex from untransfected cells. As a substrate, glutathione S-transferase (GST)-4E-BP1 expressed by bacteria is used to measure the kinase activity in the immunoprecipitates in the presence of vehicle (DMSO) or Compound 401 (1, 5 and 10 M). Samples are subjected to SDS-PAGE after kinase reactions are stopped by boiling them in SDS sample buffer. Autoradiography can identify phosphorylated 4E-BP1. Scintillation counting is used to measure the radioactivity in the bands[1].
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| References |
| Molecular Formula |
C16H15N3O2
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| Molecular Weight |
281.32
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| Exact Mass |
281.1164
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| Elemental Analysis |
C, 68.31; H, 5.37; N, 14.94; O, 11.37
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| CAS # |
168425-64-7
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| Related CAS # |
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| Appearance |
Solid powder
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| SMILES |
C1COCCN1C2=CC(=O)N3C=CC4=CC=CC=C4C3=N2
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| InChi Key |
BVRDQVRQVGRNHG-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C16H15N3O2/c20-15-11-14(18-7-9-21-10-8-18)17-16-13-4-2-1-3-12(13)5-6-19(15)16/h1-6,11H,7-10H2
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| Chemical Name |
2-morpholin-4-ylpyrimido[2,1-a]isoquinolin-4-one
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| Synonyms |
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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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 1 mg/mL (3.55 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 10.0 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of 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: 1 mg/mL (3.55 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. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 10.0 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: 1 mg/mL (3.55 mM) in 10% DMSO + 90% Corn Oil (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 | 3.5547 mL | 17.7734 mL | 35.5467 mL | |
| 5 mM | 0.7109 mL | 3.5547 mL | 7.1093 mL | |
| 10 mM | 0.3555 mL | 1.7773 mL | 3.5547 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.
Effect of compound 401 on mTOR and PI3K activitiesin vitro.J Biol Chem.2007 Aug 17;282(33):24463-70. |
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Selective inhibition of Akt Ser473phosphorylation by compound 401.J Biol Chem.2007 Aug 17;282(33):24463-70. |
Effect of compound 401 on mTOR signaling in M059J glioblastoma cells.J Biol Chem.2007 Aug 17;282(33):24463-70. |
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