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Purity: =99.23%
LY294002, a morpholine-containing compound designed based on the flavonoid quercetin, is a potent and cell-permeable PI3K inhibitor, inhibiting PI3Kα/δ/β with IC50 of 0.5 μM/0.57 μM/0.97 μM in cell-free assays, respectively. Additionally, it inhibits BET (for example, BRD2, BRD3, and BRD4). It is more stable in solutions than the PI3K inhibitor Wortmannin. By acting on the ATP binding site of the catalytic subunit of PI3K, LY294002 is selective against p110α, p110β, p110γ and p110δ.
Targets |
p110α (IC50 = 0.5 μM); p110δ (IC50 = 0.57 μM); p110β (IC50 = 0.97 μM); human CK2 (IC50 = 98 nM); human CK2α2 (IC50 = 3.869 μM); DNA-PK (IC50 = 1.4 μM)
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ln Vitro |
LY294002 is not only selective for PI3Ks; it may also act on other lipid kinases and other, seemingly unrelated proteins. Additionally to mTOR and DNA-PK, LY294002 has been demonstrated to inhibit CK2 (casein kinase 2) and Pim-1, as well as other protein kinases. Apoptosis is triggered and cell proliferation is inhibited as a result of LY294002's inactivation of Akt/PKB. In these colon cancer cell lines, LY294002 exhibits a striking growth-inhibitory and apoptosis-inducing effect, along with decreased expression of phosphorylated Akt (Ser473). [2] In tumor cells, LY294002 significantly increases nuclear pyknosis and reduces cytoplasmic volume. As a result, LY294002 significantly reduces the proliferation of ovarian cancer cells in culture. LY294002 induces specific G1 arrest in cell growth, leading to almost complete inhibition of melanoma cell proliferation and partial inhibition of MG-63 (osteosarcoma cell line) proliferation. The impact of LY294002 on cell cycle progression may shed light on a potential connection between the PI3K activation pathway and the control of the cancer cell cycle. [3]
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ln Vivo |
LY294002 exhibits remarkable effectiveness in the mouse peritonitis carcinomatosa model because it also induces apoptosis and suppresses tumor growth, particularly in LoVo tumors. [2] Ovarian carcinoma growth and ascites formation are markedly reduced by LY294002.[3] LY294002 significantly slows down the development of ascites and ovarian carcinoma.[3]
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Enzyme Assay |
PI3K inhibition by LY294002 is determined in a radiometric assay using purified, recombinant enzymes with 1μM ATP. At room temperature (24oC), the kinase reaction lasts for an hour before being stopped by the addition of PBS. Then, IC50 values are calculated by fitting a variable slope sigmoidal dose-response curve. Kinase selectivity screening is used to determine the inhibition of CK2 and GSK3β (glycogen synthase kinase 3β). In 10μM ATP, LY294002 is evaluated against the Upstate panel of kinases.
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Cell Assay |
Inoculated into 96-well microtiter plates are 1.0×105 cells (100 μL volume/well). After adding LY294002, triplicate wells are cultured at 37 °C for 0 – 48 hours. Following treatment, 10 μL of Premix WST-1 is added to each microculture well, and the plates are then incubated for 60 minutes at 37 °C. At this point, an absorbance measurement at 450 nm is made using a microplate reader.
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Animal Protocol |
Two groups of athymic nude mice (5–7 weeks) are inoculated i.p. with OVCAR-3 cells
0–100 mg/kg Administered via i.p. Athymic mice were inoculated i.p. with the ovarian cancer cell line OVCAR-3. Seven days after inoculation, mice were treated with or without LY294002 (100 mg/kg of body weight) for 3 weeks. Body weight and abdominal circumference were measured twice weekly. At the end of the experiment, mice were sacrificed, ascites volume was measured, and tumors were excised. Mean tumor burden in the LY294002-treated group was reduced by approximately 65% versus controls. Virtually no ascites developed in the treatment group; mean volume of ascites in controls was 3.3 +/- 0.38 ml. OVCAR-3 cells also were cultured in vitro without and with LY294002 (1, 5, and 10 microM) for 24 h. The number of cells in 1, 5, and 10 microM LY294002-treated wells was reduced by 27, 56, and 75%, respectively, versus controls. In vivo and in vitro morphological studies demonstrated that LY294002 induced marked nuclear pyknosis and diminished cytoplasmic volume in the tumor cells, confirmed as apoptosis. Thus, LY294002 significantly inhibits growth and ascites formation of ovarian carcinoma in vivo and markedly inhibits ovarian cancer cell proliferation in vitro, suggesting an important role of PI3-K inhibitors as a potentially useful treatment for women with ovarian carcinoma.[3] |
References | |
Additional Infomation |
LY294002 is a chromone substituted with a phenyl group at position 8 and a morpholine group at position 2. It has a role as an EC 2.7.1.137 (phosphatidylinositol 3-kinase) inhibitor, an autophagy inhibitor and a geroprotector. It is a member of chromones, a member of morpholines and an organochlorine compound.
Specific inhibitor of phosphatidylinositol 3-kinase.
2-(4-Morpholinyl)-8-phenyl-4H-1-benzopyran-4-one is a natural product found in Hexagonia apiaria and Dietes bicolor with data available.
PI3K/BET Inhibitor LY294002 is a morpholine-based inhibitor of phosphatidylinositol 3-kinase (PI3K) and the bromodomain and extra-terminal (BET) family of proteins, with potential antineoplastic activity. Upon administration, the PI3K/BET inhibitor LY294002 specifically targets and binds to both PI3K and the acetylated lysine recognition motifs in the bromodomains of BET proteins. Inhibition of PI3K activity inhibits the PI3K/AKT kinase signaling pathway. This may result in inhibition of growth and survival for tumor cells in which the PI3K-mediated signaling pathway is overactivated. Inhibition of BET proteins prevents their interaction with acetylated histones, disrupts chromatin remodeling and inhibits the expression of oncogenic drivers that are important for cell proliferation and survival, which together may lead to an inhibition of proliferation in BET-overexpressing tumor cells. Activation of the PI3K signaling pathway is frequently associated with tumorigenesis. BET proteins, comprised of BRD2, BRD3, BRD4 and BRDT, are transcriptional regulators and play an important role during development and cellular growth. In tumor cells, BET proteins play a key role in the regulation of oncogene transcription and tumor cell proliferation. |
Molecular Formula |
C19H17NO3
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Molecular Weight |
307.3432
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Exact Mass |
307.12084
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Elemental Analysis |
C, 74.25; H, 5.58; N, 4.56; O, 15.62
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CAS # |
154447-36-6
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Related CAS # |
LY294002 hydrochloride;934389-88-5
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PubChem CID |
3973
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Appearance |
White to yellow solid powder
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Density |
1.3±0.1 g/cm3
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Boiling Point |
494.6±45.0 °C at 760 mmHg
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Melting Point |
182-184ºC
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Flash Point |
253.0±28.7 °C
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Vapour Pressure |
0.0±1.3 mmHg at 25°C
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Index of Refraction |
1.627
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LogP |
3.8
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tPSA |
42.68
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SMILES |
C1COCCN1C2=CC(=O)C3=C(O2)C(=CC=C3)C4=CC=CC=C4
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InChi Key |
CZQHHVNHHHRRDU-UHFFFAOYSA-N
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InChi Code |
InChI=1S/C19H17NO3/c21-17-13-18(20-9-11-22-12-10-20)23-19-15(7-4-8-16(17)19)14-5-2-1-3-6-14/h1-8,13H,9-12H2
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Chemical Name |
2-morpholin-4-yl-8-phenylchromen-4-one
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Synonyms |
LY-294002; LY 294002; LY294002
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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: ~36 mg/mL (117.1 mM)
Water: <1 mg/mL (slightly soluble or insoluble) Ethanol: ~21 mg/mL (~68.3 mM) |
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Solubility (In Vivo) |
Solubility in Formulation 1: 2.87 mg/mL (9.34 mM) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
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. Solubility in Formulation 2: ≥ 2.25 mg/mL (7.32 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 22.5 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: ≥ 2.25 mg/mL (7.32 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. Solubility in Formulation 4: ≥ 2.25 mg/mL (7.32 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 22.5 mg/mL clear DMSO stock solution to 900 μL corn oil and mix evenly. Solubility in Formulation 5: 4%DMSO+30%PEG 300+5%Tween 80+ddH2O: 5mg/mL Solubility in Formulation 6: 15.71 mg/mL (51.12 mM) in 0.5% CMC-Na/saline water (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. |
Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
1 mM | 3.2537 mL | 16.2686 mL | 32.5373 mL | |
5 mM | 0.6507 mL | 3.2537 mL | 6.5075 mL | |
10 mM | 0.3254 mL | 1.6269 mL | 3.2537 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.
Pharmacological inhibition of GSK-3 kinase activity blunts antiviral innate immunity. Mol Cell Biol. 2015 Sep 1;35(17):3029-43. td> |
Absence of GSK-3 does not affect IRF3 activation. td> |