| Size | Price | Stock | Qty |
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| 25mg |
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| 50mg |
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| 100mg |
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| 250mg |
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PI-103 Hydrochloride (PI 103; PI103), the hydrochloride salt of PI-103, is a multi-targeted PI3K and mTOR inhibitor with potential antineoplastic activity. It inhibits p110α/β/δ/γ with IC50s of 2 nM/3 nM/3 nM/15 nM in cell-free assays, and is less potent against mTOR/DNA-PK with IC50 of 30 nM/23 nM. In vitro tests with cancer cell lines from the prostate, ovary, and glioblastoma demonstrate the potent anti-proliferative activity of PI-103. Against U87MG, IGROV-1, DETROIT-562, PC3, SKOV-3, and HUVEC cells, it had antiproliferative GI50 values of 0.14, 0.06, 0.13, 0.10, 0.12, and 0.08 M, respectively.
| Targets |
p110α (IC50 = 2 nM); p110β (IC50 = 3 nM); p110δ (IC50 = 3 nM); p110γ (IC50 = 15 nM); mTORC1 (IC50 = 20 nM); mTORC2 (IC50 = 83 nM); DNA-PK (IC50 = 23 nM)
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| ln Vitro |
PI-103 potently inhibits both the rapamycin-sensitive (mTORC1) and rapamycin-insensitive (mTORC2) complexes of the protein kinase mTOR.[1] PI-103 blocks PI3K/Akt activation that is both intrinsically occurring and induced by growth factors. [2] In blast cells, PI-103 prevents leukemia from proliferating, prevents leukemia progenitors from cloning, and triggers mitochondrial apoptosis, particularly in the compartment housing leukemia stem cells. PI-103 inhibits p110α more effectively than p110 by a factor of >200-fold. Additionally, PI-103 effectively inhibits the synthesis of PIP3 and PI(3,4)P2 in myotubes and adipocytes, respectively. [2] With an IC95 100 times lower than that of LY294002, PI-103 inhibits Akt phosphorylation. Surprisingly, PI-103 completely shields animals from the decline in blood sugar caused by insulin. In blast cells and immature leukemic cells, PI-103 has proapoptotic effects that are additive to those of etoposide. [2]
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| ln Vivo |
When tumors reach 50-100 mm3, animals are randomized and treated with vehicle or PI-103. After 18 days, PI-103 shows significant activity, with an average 4-fold reduction in tumor size. [2] Premorbidly (based on body weight, amount of food and water consumed, activity level, and general exam) or at necropsy, mice treated with PI-103 show no overt toxic effects. As expected from the blockade of p110α and mTOR, treated tumors show lower levels of phosphorylated Akt and S6. Treatment with PI-103 is cytostatic to glioma xenografts. [2]
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| Enzyme Assay |
IC50 values are measured using either a standard thin-layer chromatography (TLC) assay for lipid kinase activity or a high-throughput membrane capture assay. Kinase reactions are performed by preparing a reaction mixture containing kinase, inhibitor (2% DMSO final concentration), buffer (25 mM HEPES, pH 7.4, 10 mM MgCl2), and freshly sonicated phosphatidylinositol (100 μg/mL). Reactions are initiated by the addition of ATP containing 10 μCi of γ-32P-ATP to a final concentration 10 or 100 μM, and allowed to proceed for 20 minutes at room temperature. For TLC analysis, reactions are then terminated by the addition of 105 μL 1N HCl followed by 160 μL CHCl3:MeOH (1:1). The biphasic mixture is vortexed, briefly centrifuged, and the organic phase transferred to a new tube using a gel loading pipette tip precoated with CHCl3. This extract is spotted on TLC plates and developed for 3-4 hours in a 65:35 solution of n-propanol:1M acetic acid. The TLC plates are then dried, exposed to a phosphorimager screen, and quantitated. For each compound, kinase activity is typically measured at 10-12 inhibitor concentrations representing two-fold dilutions from the highest concentration tested (100 μM). For compounds showing significant activity, IC50 determinations are repeated two to four times, and the reported value is the average of these independent measurements.
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| Cell Assay |
An Invitrogen TR-FRET-based LanthaScreen technique was used to assess the inhibition of the mTOR protein kinase. In order to calculate the IC50 values, compounds were tested at a maximum concentration of 10 mol/L in the presence of 1 μmol/L ATP.
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| Animal Protocol |
Mice: Males aged five to six months are subcutaneously injected with one million cells in PBS, either from the FVB/N strain or the nude BALB/c strain. Mice are given daily injections of 50 mg/kg sorafenib and/or 10 mg/kg or 70 mg/kg of PI-103 when the tumor has grown to between 50 and 100 mm3. The same amount of DMSO is administered to control mice. Every two days, mice weight and tumor size are measured. Tumors are removed from mice after they have died and processed.
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| References |
| Molecular Formula |
C₁₉H₁₇CLN₄O₃
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|---|---|
| Molecular Weight |
384.82
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| Elemental Analysis |
C, 59.30; H, 4.45; Cl, 9.21; N, 14.56; O, 12.47
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| CAS # |
371935-79-4
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| Related CAS # |
PI-103;371935-74-9
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| Appearance |
Solid
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| SMILES |
C1COCCN1C2=NC(=NC3=C2OC4=C3C=CC=N4)C5=CC(=CC=C5)O.Cl
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| InChi Key |
XSQMYBFFYPTMFE-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C19H16N4O3.ClH/c24-13-4-1-3-12(11-13)17-21-15-14-5-2-6-20-19(14)26-16(15)18(22-17)23-7-9-25-10-8-23;/h1-6,11,24H,7-10H2;1H
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| Chemical Name |
3-(6-morpholin-4-yl-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3,5,10,12-hexaen-4-yl)phenol;hydrochloride
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| Synonyms |
PI-103 hydrochloride; PI-103 HCl; PI 103 HCl; PI103 HCl
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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: 4.1~24 mg/mL (10.7~68.9 mM)
Ethanol: ~19.7 mg/mL (~60.2 mM) |
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| Solubility (In Vivo) |
5%DMSO+40%PEG300+5%Tween80+50%ddH2O: 1 mg/mL (Please use freshly prepared in vivo formulations for optimal results.)
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| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5986 mL | 12.9931 mL | 25.9862 mL | |
| 5 mM | 0.5197 mL | 2.5986 mL | 5.1972 mL | |
| 10 mM | 0.2599 mL | 1.2993 mL | 2.5986 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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