Gedatolisib (PF-05212384, PKI-587) 化学構造
分子量: 615.73

品質と確認

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Quality Control & MSDS

製品情報

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    PI3K阻害剤を比較
  • 研究分野
  • Combination Therapy
    併用療法

製品の説明

生物活性

情報 Gedatolisib (PF-05212384, PKI-587)は、PI3K-α、PI3K-γとmTORの非常に強力な多-キナーゼ阻害剤で、IC50 がそれぞれ 0.4 nM、 5.4 nM 、 1.6 nMです。
目標 PI3K-α PI3K-γ mTOR
IC50 0.4 nM 5.4 nM 1.6 nM [1]
In vitro試験 PKI-587 shows potent inhibitory activity against PI3K-α, PI3K-γ and mTOR with IC50 of 0.4 nM, 5.4 nM and 1.6 nM, respectively. Furthermore, PKI-587 also exhibits its potency against the most frequently occurring mutant forms of PI3Kα, notably the H1047R and E545K with IC50 of 0.6 nM and 0.6 nM, respectively. [1] Correlated with suppression of phosphorylation of PI3K/mTOR signaling pathway proteins, PKI-587 causes tumor cell growth inhibition in MDA-361 and PC3-MM2 cell lines with IC50 of 4 nM and 13.1 nM, respectively. [1]
In vivo試験 In nude mice, PKI-587 treatment at 25 mg/kg iv leads to low plasma clearance (7 (mL/min)/kg), high volume of distribution (7.2 L/kg), and long half-life, (14.4 hours). In the MDA-361 xenograft model, PKI-587 produces potent antitumor efficacy with the minimum efficacious dose (MED) of 3 mg/kg against MDA-361 tumors and maximum tolerated single dose (MTD) of 30 mg/kg. While in the H1975 (non-small-cell lung carcinoma, mutant EGFR [L858R, T790M]) xenograft model, PKI-587 at 25 mg/kg for 7 weeks results in 90% survival of the group treated. [1]
臨床試験 PKI-587 is currently in Phase I clinical trials in patients with solid tumors.
特集

推薦された実験操作 (公開の文献だけ)

キナーゼアッセイ: [1]

PI3K and mTOR kinase assay Enzyme assays are done in fluorescent polarization (FP) format, adapted from the Echelon K-1100 PI3K FP assay kit protocol. Human class I PI3Ks and PI3K-α mutants (E545K and H1047R) are produced in Sf9 or purchased from Upstate Biotech. GST-GRP1 (murine) is produced in Escherichia coli and isolated by GST-Sepharose. Assay buffers are reaction buffer [20 mM HEPES (pH 7.1), 2 mM MgCl2, 0.05% CHAPS, and 0.01% β-mercaptoethanol] and stop/detection buffer [100 mM HEPES (pH 7.5), 4 mM EDTA, 0.05% CHAPS]. FP reaction is run for 30 minutes at room temperature in 20 μL of reaction buffer containing 20 μM phosphatidylinositol 4,5-bisphosphate (PIP2), 25 μM ATP, and <4% DMSO. FP reaction is stopped with 20 μL of stop/detection buffer (10 nM probe and 40 nM GST-GRP), and after 2 hours, data are collected using an Envision plate reader. The routine assays with purified FLAG-TOR (FL and 3.5) are performed in 96-well plates as follows. Enzymes are first diluted in kinase assay buffer (10 mM Hepes (pH 7.4), 50 mM NaCl, 50 mM β-glycerophosphate, 10 mM MnCl2, 0.5 mM DTT, 0.25 μM microcystin LR, and 100 μg/mL BSA). To each well, 12 μL of the diluted enzyme is mixed briefly with 0.5 μL test inhibitor or control vehicle dimethyl sulfoxide (DMSO). The kinase reaction is initiated by adding 12.5 μL kinase assay buffer containing ATP and His6-S6K to give a final reaction volume of 25 μL containing 800 ng/mL FLAG-TOR, 100 μM ATP, and 1.25 μM His6-S6K. The reaction plate is incubated for 2 hours (linear at 1–6 hours) at room temperature with gentle shaking and then terminated by adding 25 μL Stop buffer (20 mM Hepes (pH 7.4), 20 mM EDTA, and 20 mM EGTA).

細胞アッセイ: [1]

細胞系 MDA-361 and PC3-MM2
濃度 0-10 μM
処理時間 72 hours
方法 Cells are plated in 96-well culture plates at about 3000 cells per well. One day following plating, PKI-587 is added to cells. Three days after PKI-587 treatment, viable cell densities are determined by measuring metabolic conversion (by viable cells) of the dye MTS, a previously established cell proliferation assay. For each assay, MTS and PMS stocks are freshly thawed and mixed (MTS/PMS, 20:1). The MTS/PMS mixture is then added to 96-well cell plates at 20 μL/well, and plates are incubated for 1 hour–2 hours in cell culture incubator. MTS assay results are read in a 96-well format plate reader by measuring absorbance at 490 nm. The effect of each PKI-587 treatment is calculated as a percentage of control cell growth obtained from vehicle-treated cells grown in the same culture plate.

動物実験: [1]

動物モデル MDA-361 and H1975 cells are injected subcutaneously into the nude mice.
製剤 Dissolved in 5% dextrose [D5/W], 0.3% lactic acid.
投薬量 ≤30 mg/kg
管理 Administered via i.v.

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

SpeciesMouseRatRabbitGuinea pigHamsterDogMonkeyBaboon
Weight (kg)0.020.151.80.40.0810312
Body Surface Area (m2)0.0070.0250.150.050.020.50.240.6
Km factor361285201220
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 Gedatolisib (PF-05212384, PKI-587) SDF
分子量 615.73
化学式

C32H41N9O4

CAS No. 1197160-78-3
保管 2年-20℃
6月-80℃in solvent
別名 N/A
溶解度 (25°C) * In vitro DMSO 2 mg/mL (3.24 mM)
<1 mg/mL (<1 mM)
エタノール <1 mg/mL (<1 mM)
* <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 1-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)-3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)urea

研究分野

カスタマーレビュー (2)


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Source Pigment Cell Melanoma Res, 2014, 27(5), 813-21. Gedatolisib (PF-05212384, PKI-587) purchased from Selleck
Method Western blotting
Cell Lines A2058, D28, HT144, D20, SKMel13 cells
Concentrations 5 uM
Incubation Time 2 h
Results The three-fold difference in the IC50 values for the PI3K inhibitors was reflected in the different outcomes of PI3K inhibition. The checkpoint-functional tumour sphere cultures displayed lower levels of cell death than the checkpoint-defective lines when treated with 5 uM PF-05212384 for 72 h. This produced strong inhibition of PI3K activity as measured by pAkt Ser473 in all lines, although all the checkpoint-defective line displayed three-fold higher levels of basal pAkt.

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Rating
Source Dr. Zhang of Tianjin Medical University. Gedatolisib (PF-05212384, PKI-587) purchased from Selleck
Method Western Blot
Cell Lines A549 cells
Concentrations 0-10 μM
Incubation Time 3 h
Results PKI-587 treatment resulted in a reduction of AKT phosphorylation.

製品表彰状 (1)

技術サポート&よくある質問(FAQ)

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