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Purity: ≥98%
PI-103 is a novel and potent multi-targeted PI3K inhibitor for p110α/β/δ/γ with IC50 of 2 nM/3 nM/3 nM/15 nM in cell-free assays, and has anticancer activity. With an IC50 of 30 nM/23 nM, it is less effective against mTOR and DNA-PK. In numerous cancer cell lines, including those from the prostate, ovary, and glioblastoma, PI-103 demonstrated strong antiproliferation activities. In U87MG, IGROV-1, DETROIT-562, PC3, SKOV-3, and HUVEC cells, it had GI50 values of 0.14, 0.06, 0.13, 0.10, 0.12, and 0.08 M, respectively.
| Targets |
p110α (IC50 = 8 nM); p110β (IC50 = 88 nM); p110δ (IC50 = 48 nM); p110γ (IC50 = 150 nM); mTORC1 (IC50 = 20 nM); mTORC2 (IC50 = 83 nM); PI3KC2β (IC50 = 26 nM); PI3KC2α (IC50 = 1 μM); hsVPS34 (IC50 = 2.3 μM); DNA-PK (IC50 = 2 nM); ATR (IC50 = 850 nM); ATM (IC50 = 920 nM); PI4KIIIβ (IC50 = 50 μM)
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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 >200-fold more potently than p110β. 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 |
Animals are treated with either vehicle or PI-103 when tumors measure 50 to 100 mm3. 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 |
Phosphatidylinositide 3-kinase inhibitory activity was determined using a scintillation proximity assay in the presence of 1 μmol/L ATP. A TR-FRET-based LanthaScreen technique from Invitrogen was used to determine whether mTOR protein kinase was inhibited. Using GraphPad Prism software, IC50 values were calculated for each compound at a maximum concentration of 10 mol/L in the presence of 1 mol/L ATP.[1]
Protein Kinase Assays[1] Abl, Abl (T315I) Inhibitors (final concentration: 10 μM) were assayed in triplicate against recombinant full-length Abl or Abl (T315I) (Upstate) in an assay containing 25 mM HEPES, pH 7.4, 10 mM MgCl2, 200 μM ATP (2.5 μCi of γ-32P-ATP), and 0.5 mg/mL BSA. The optimized Abl peptide substrate EAIYAAPFAKKK was used as phosphoacceptor (200 μM). Reactions were terminated by spotting onto phosphocellulose sheets, which were washed with 0.5% phosphoric acid (approximately 6 times, 5-10 minutes each). Sheets were dried and the transferred radioactivity quantitated by phosphorimaging. [1] Akt1, Akt1 (ΔPH), Akt2, Akt2 (ΔPH), Akt3 (ΔPH) [1] Inhibitors (final concentration: 10 μM) were assayed in triplicate against recombinant full-length Akt1, Akt2, Akt3, Akt1 (ΔPH), or Akt2 (ΔPH) in an assay containing 25 mM HEPES, pH 7.4, 10 mM MgCl2, 200 μM ATP (2.5 μCi of γ-32P-ATP), and 0.5 mg/mL BSA. Myelin basic protein (0.2 mg/mL) was used as a substrate. Reactions were terminated by spotting onto nitrocellulose, which was washed with 1M NaCl/1% phosphoric acid (approximately 6 times, 5-10 minutes each). Sheets were dried and the transferred radioactivity quantitated by phosphorimaging.[1] Fore more kinase assay, please refer to the SI of this article (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2946820/). |
| Cell Assay |
PI-103 is applied to U87MG cells for 24 hours. Using a cytotoxicity detection kit and a colorimetric determination of LDH activity, cell death is measured. Calculating the percentage of cell death (mean of three 12-well plates per experimental point) is calculated [(experimental value- low control)/(high control -low control) × 100], where the low control is treated with DMSO and the high control with Triton (1% Triton X-100, 30 min, 37 °).
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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. When a tumor grows to a size between 50 and 100 mm3, mice are given either 10 mg/kg or 70 mg/kg of PI-103 intraperitoneally (IP) every day. 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 | |
| Additional Infomation |
PI-103 is an organic heterotricyclic compound that is pyrido[3',2':4,5]furo[3,2-d]pyrimidine substituted at positions 2 and 4 by 3-hydroxyphenyl and morpholin-4-yl groups respectively. A dual-kinase inhibitor with anti-cancer properties. It has a role as an EC 2.7.1.137 (phosphatidylinositol 3-kinase) inhibitor, a mTOR inhibitor and an antineoplastic agent. It is a member of morpholines, a member of phenols, an organic heterotricyclic compound, a tertiary amino compound and an aromatic amine.
PI-103 is an inhibitor of p110α of class I PI3K. |
| Molecular Formula |
C19H16N4O3
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|---|---|
| Molecular Weight |
348.36
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| Exact Mass |
384.8163
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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 # |
371935-74-9
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| Related CAS # |
PI-103 Hydrochloride;371935-79-4; 371935-79-4 (HCl); 371935-74-9
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| PubChem CID |
9884685
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| Appearance |
Light yellow to green yellow solid powder
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| Density |
1.409 g/cm3
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| Boiling Point |
520.25ºC at 760 mmHg
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| Index of Refraction |
1.712
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| LogP |
3.847
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
2
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| Heavy Atom Count |
26
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| Complexity |
489
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O1C([H])([H])C([H])([H])N(C2C3=C(C4C([H])=C([H])C([H])=NC=4O3)N=C(C3C([H])=C([H])C([H])=C(C=3[H])O[H])N=2)C([H])([H])C1([H])[H]
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| InChi Key |
TUVCWJQQGGETHL-UHFFFAOYSA-N
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| InChi Code |
nChI=1S/C19H16N4O3/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
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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
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| Synonyms |
UNII-YQX02F616F; Phenol, 3-[4-(4-morpholinyl)pyrido[3',2':4,5]furo[3,2-d]pyrimidin-2-yl]-;
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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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1.05 mg/mL (3.01 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 10.5 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. Solubility in Formulation 2: ≥ 1.05 mg/mL (3.01 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 10.5 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. View More
Solubility in Formulation 3: 1% DMSO +30% polyethylene glycol+1% Tween 80 : 30mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.8706 mL | 14.3530 mL | 28.7059 mL | |
| 5 mM | 0.5741 mL | 2.8706 mL | 5.7412 mL | |
| 10 mM | 0.2871 mL | 1.4353 mL | 2.8706 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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Cooperative inhibition of p110α and mTOR arrests growth of human glioma cells.Cancer Cell.2006 May;9(5):341-9. |
Inhibition of p110α and of mTOR represents a safe and effective strategy in EGFR-driven glioma in vitro and in vivo.Cancer Cell.2006 May;9(5):341-9. |
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