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| 5mg |
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| 25mg |
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| 100mg |
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Purity: ≥98%
LY303511 is an analog of LY294002 and is also known as NV-128 and EM 101. LY303511 is a powerful mTOR inhibitor, in contrast to LY294002, which is a BET/PI3K inhibitor. Without harming PI3K, LY303511 reduces mTOR-dependent cell proliferation. Like rapamycin, LY303511 inhibited mTOR-dependent phosphorylation of S6K in human lung epithelial adenocarcinoma (A549) cells, but not PI3K-dependent phosphorylation of Akt. Without inducing apoptosis, LY303511 inhibited proliferation in A549 and primary pulmonary artery smooth muscle cells. LY303511 inhibited G(2)/M progression and G(2)/M-specific cyclins in A549 cells, in contrast to rapamycin. LY303511 reduced the activity of casein kinase 2, a known regulator of G(1) and G(2)/M progression, which is consistent with its inhibition of another mTOR-independent kinase target. In addition to having an antiproliferative effect in vitro, LY303511 also prevented athymic mice from developing human prostate adenocarcinoma tumor implants. LY303511 has therapeutic potential with antineoplastic effects that are independent of PI3K inhibition because it inhibits cell proliferation via mTOR-dependent and independent mechanisms.
| Targets |
TRAIL (IC50 = 64.6±9.1 µM)
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| ln Vitro |
LY303511 does not potently inhibit PI3K despite sharing a structural similarity with LY294002 other than the substitution of -O for -NH in the morpholine ring. When cells are treated with LY303511, calcein spread rises to levels similar to those of LY294002. AKT phosphorylation is inhibited by LY303511, but this effect does not coincide with increased gap junctional intercellular communication (GJIC), as determined by immunoblotting[1]. By activating H2O2-MAPK and upregulating death receptors, the drug LY303511 makes SHEP-1 neuroblastoma cells more susceptible to the effects of TRAIL. SHEP-1 cells are exposed to LY303511 (LY30), TRAIL, and a combination of the two (1 hour of LY303511 preincubation followed by 4 hours of TRAIL exposure) at various concentrations. Although LY303511 (12.5, 25, or 50 μM) treatment has no impact on cell viability, SHEP-1 cells are responsive to TRAIL (10%, 15%, and 30% reduction in the surviving fraction at 25, 50, and 100 ng/mL, respectively). The combination of LY303511 (25 M) and TRAIL (50 ng/mL) for 4 hours, followed by the incubation of the cells, has a strong synergistic effect (40% reduction in viable cells with LY303511+TRAIL versus 15% with TRAIL alone)[2]. Regarding PI3K activity, LY303511 serves as a negative control substance. Wortmannin (100 nM) in MIN6 insulinoma cells has no effect on whole-cell outward K+ currents, but LY294002 and LY303511 reversibly block currents in a dose-dependent manner (IC50=9.0±0.7 μM and 64.6±9.1 μM, respectively). Beta cells have high levels of Kv2.1 and Kv1.4 expression. In Kv2.1-transfected tsA201 cells, LY294002 and LY303511 reversibly inhibit currents by ~90 and 41%, respectively. LY303511 inhibits currents with an IC50 of 64.6±9.1 µM and a maximum inhibitory concentration of 500 μM (n≥5 cells at each concentration)[3].
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| ln Vivo |
Intraperitoneal administration of vehicle or LY303511 (10 mg/kg/day) is performed when tumors reach a volume of ~150 mm3, at which time 35 mice have developed a tumor. Since the average tumor volume was estimated to be unreliable, the data were censored after 21 days because >15% of the mice needed to be put to sleep due to excessive tumor growth. The PC-3 tumor can be prevented from growing in vivo by administering LY303511 at a dose of 10 mg/kg/day[4].
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| Enzyme Assay |
LY303511 is structurally identical to LY294002 except for a substitution of -O for -NH in the morpholine ring, and does not potently inhibit PI3K. Treatment of cells with LY303511 causes an increase in calcein spread similar to levels of LY294002. The ability of LY303511 to increase gap junctional intercellular communication (GJIC) does not occur concomitant with inhibition of phosphorylation of AKT as measured by immunoblotting.
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| Cell Assay |
Human neuroblastoma SHEP-1 cells are maintained in DMEM supplemented with 10% fetal bovine serum and 1% Penicillin. In a typical survival assay, LY303511 (12.5, 25, and 50 μM), TRAIL (25, 50, and 100 ng/mL), and a combination of the two (1 h preincubation with LY303511 followed by TRAIL for 4 h) are exposed to SHEP-1 cells (8×104 per well) plated in 24-well plates for 24 h. The crystal violet assay is used to determine cytotoxicity. Following drug exposure, cells are PBS washed and then incubated with 200 μL of crystal violet solution for 20 min. The remaining crystals are dissolved in 20% acetic acid after the excess crystal violet solution has been removed with distilled water. Using an automated ELISA reader, absorbance at 595 nm wavelength is used to assess viability. Cell viability experiments are performed similarly with 2,000 units/mL of catalase, 4 μM JNK inhibitor SP600125, 10 μM p38 inhibitor SB202190, 20 μM MAPK/ERK kinase (MEK) inhibitor PD98059, 50 μM of caspase-8 inhibitor Z-IETD-FMK or pan-caspase inhibitor Z-VAD-FMK, or death receptor blocking antibodies (4 μg/mL anti-DR4 or 1 μg/mL anti-DR5), or in cells transfected with small interfering RNA (siRNA) for silencing JNK and ERK expression, respectively. Before adding TRAIL, cells are pre-incubated for 1 hour with LY303511 and the appropriate inhibitor or catalase.
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| Animal Protocol |
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| References |
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| Molecular Formula |
C₁₉H₁₉CLN₂O₂
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| Molecular Weight |
342.82
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| Exact Mass |
342.1135055
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| CAS # |
2070014-90-1
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| Related CAS # |
LY 303511;154447-38-8
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| Appearance |
Solid
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| SMILES |
C1CN(CCN1)C2=CC(=O)C3=C(O2)C(=CC=C3)C4=CC=CC=C4.Cl
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| InChi Key |
QGVSIVYHHKLHPY-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C19H18N2O2.ClH/c22-17-13-18(21-11-9-20-10-12-21)23-19-15(7-4-8-16(17)19)14-5-2-1-3-6-14;/h1-8,13,20H,9-12H2;1H
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| Chemical Name |
8-phenyl-2-piperazin-1-ylchromen-4-one;hydrochloride
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| Synonyms |
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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: ≥ 2.5 mg/mL (7.29 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 (7.29 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.9170 mL | 14.5849 mL | 29.1698 mL | |
| 5 mM | 0.5834 mL | 2.9170 mL | 5.8340 mL | |
| 10 mM | 0.2917 mL | 1.4585 mL | 2.9170 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.
 LY30 can reduce cell proliferation and sensitize cells treated with low doses of vincristine to apoptosis via an increase in caspase activity.Cancer Res.2005 Jul 15;65(14):6264-74. |
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 LY30 can reduce cell proliferation and sensitize cells treated with low doses of vincristine to apoptosis via an increase in caspase activity.Cancer Res.2005 Jul 15;65(14):6264-74. |
 LY30 inhibits the colony-forming ability of cells treated with vincristine.Cancer Res.2005 Jul 15;65(14):6264-74. |
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