PI-103

PI-103は、強力な、細胞透過性、ATP競争的クラスI PI3K阻害剤で、DNA-PK、 p110α、 mTORC1、 PI3-KC2β、 p110δ、 mTORC2、 p110β、p110γ に作用すると、IC50 がそれぞれ 2 nM、 8 nM、 20 nM、26 nM、 48 nM、 83 nM、 88 nM 、150 nMになる。

目録号S1038
5 5 4レビュー 18製品表彰状
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PI-103 化学構造
分子量: 348.36

品質と確認

カスタマーレビュー(4)

Quality Control & MSDS

製品情報

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  • 研究分野
  • PI-103のメカニズム

製品の説明

生物活性

情報 PI-103は、強力な、細胞透過性、ATP競争的クラスI PI3K阻害剤で、DNA-PK、 p110α、 mTORC1、 PI3-KC2β、 p110δ、 mTORC2、 p110β、p110γ に作用すると、IC50 がそれぞれ 2 nM、 8 nM、 20 nM、26 nM、 48 nM、 83 nM、 88 nM 、150 nMになる。
目標 p110α p110β p110δ p110γ mTOR DNA-PK
IC50 2 nM 3 nM 3 nM 15 nM 30 nM 23 nM [3]
In vitro試験 PI-103 potently inhibits both the rapamycin-sensitive (mTORC1) and rapamycin-insensitive (mTORC2) complexes of the protein kinase mTOR. [1] PI-103 inhibits constitutive and growth factor-induced PI3K/Akt, as well as mTORC1 activation. [2] In blast cells, PI-103 inhibits leukemic proliferation, the clonogenicity of leukemic progenitors and induces mitochondrial apoptosis, especially in the compartment containing leukemic stem cells. PI-103 inhibits p110α >200-fold more potently than p110β. PI-103 also potently blocks production of PI(3,4)P2 and PIP3 in adipocytes and PIP3 in myotubes. [2] PI-103 inhibits phosphorylation of Akt with an IC95 100-fold lower than that for LY294002. Strikingly, PI-103 completely protects animals from insulin-stimulated decline in blood glucose. PI-103 has additive proapoptotic effects with etoposide in blast cells and in immature leukemic cells. [2]
In vivo試験 When tumors reach 50-100 mm3, animals are randomized and treated with vehicle or PI-103. PI-103 exhibits significant activity, decreasing average tumor size by 4-fold after 18 days. [2] Mice treated with PI-103 have no obvious signs of toxicity premorbidly (based on body weight, food and water intake, activity, and general exam) or at necropsy. Treated tumors display decreased levels of phosphorylated Akt and S6, consistent with blockade of p110α and mTOR. PI-103 treatment is cytostatic to glioma xenografts. [2]
臨床試験
特集 The first potent, synthetic mTOR inhibitor.

推薦された実験操作 (公開の文献だけ)

キナーゼアッセイ: [3]

Enzyme Assays Phosphatidylinositide 3-kinase inhibitory activity was determined using a scintillation proximity assay in the presence of 1 μmol/L ATP. Inhibition of mTOR protein kinase was determined using a TR-FRET-based LanthaScreen method from Invitrogen. Compounds were assayed at a maximum concentration of 10 μmol/L in the presence of 1 μmol/L ATP, and IC50 values were determined using GraphPad Prism software.

細胞アッセイ: [2]

細胞系 U87MG cells
濃度 0.5 μM
処理時間 24 hours
方法 U87MG cells are treated with PI-103 for 24 hours. Cell death is quantified by colorimetric determination of LDH activity using a cytotoxicity detection kit. 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 cells are DMSO treated and high-control cells are Triton treated (1% Triton X-100, 30 min, 37 °

動物実験: [2]

動物モデル 6- to 12-week-old Balbc nu/nu mice bearing U87MG:ΔEGFR cells
製剤 50% DMSO
投薬量 5 mg/kg
管理 Administered via i.p.
Solubility 1% DMSO/30% polyethylene glycol/1% Tween 80 30 mg/mL
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesBaboonDogMonkeyRabbitGuinea pigRatHamsterMouse
Weight (kg)121031.80.40.150.080.02
Body Surface Area (m2)0.60.50.240.150.050.0250.020.007
Km factor202012128653
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

参考

化学情報

Download PI-103 SDF
分子量 348.36
化学式

C19H16N4O3

CAS No. 371935-74-9
保管 2年-20℃
6月-80℃in DMSO
別名
溶解度 (25°C) * In vitro DMSO 24 mg/mL (68.89 mM)
<1 mg/mL (<1 mM)
エタノール <1 mg/mL (<1 mM)
In vivo 1% DMSO/30% polyethylene glycol/1% Tween 80 30 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
化学名 Phenol, 3-[4-(4-morpholinyl)pyrido[3',2':4,5]furo[3,2-d]pyrimidin-2-yl]-

研究分野

カスタマーレビュー (4)


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Rating
Source Mol Carcinog, 2012, 52, 667-75 . PI-103 purchased from Selleck
Method Western blot
Cell Lines MCF7 cells
Concentrations 0-1 μM
Incubation Time 24 h
Results In BRCA1-KD MCF7 cells, treatment of PI-103, a PI3K/mTOR inhibitor, abolished phosphorylation of AKT and its substrate GSK3b, in a dose dependent manner (Figure A). Treatment of PI-103 reduced the phosphorylation of AKT in all BRCA1 mutant breast cancer cells tested (Figure B). Phosphorylations of downstream targets of AKT, such as phospho-GSK3b (S9) and phospho-BAD(S112) were also reduced by PI-103 treatment. Phosphorylation of mTOR at S2448, which is also known to be phosphorylated by AKT, was also reduced by PI-103 resulting in reduced phosphorylation of S6 ribosomal protein at S235/236 (Figure B). The effect of PI-103 was much more potent than LY294002 in MDA-MB-436 cells (Figure B)

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Rating
Source Mol Carcinog, 2012, ahead of print. PI-103 purchased from Selleck
Method MTT assay
Cell Lines MCF7 cells
Concentrations 0.01-1 μM
Incubation Time 48 h
Results Knockdown of BRCA1 can sensitize the MCF7 cells to Perifosine in a dose-dependent manner (Figure A). BRCA1-KD also sensitizes the MCF7 cells to dual PI3K/mTOR inhibitors, such as PI-103 or BEZ235 (Figure B, D). Another inhibitor, PIK-75 which specifically inhibits PI3Ka and PI3Kg, but not mTOR, also showed similar effects on proliferation of BRCA1-KD MCF7 cells (Figure C).

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Rating
Source Dr. Zhang of Tianjin Medical University. PI-103 purchased from Selleck
Method Western blot
Cell Lines Breast cancer cells
Concentrations 0-1 nM
Incubation Time 24 h
Results PI-103 treatment resulted in a reduction of Akt phosphorylation in Breast cancer cells.

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Rating
Source Saraswati Sukumar of Johns Hopkins University School of Medicine, PI-103 purchased from Selleck
Method Western blot
Cell Lines T47D cells
Concentrations
Incubation Time 1 h
Results PI-103 treatment resulted in a reduction of Akt phosphorylation in T47D cells.

製品表彰状 (18)

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