PF-04691502 化学構造
分子量: 425.48

品質と確認

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Quality Control & MSDS

製品情報

  • Compare PI3K Inhibitors
    PI3K阻害剤を比較
  • 研究分野
  • Combination Therapy
    併用療法
  • PF-04691502のメカニズム

製品の説明

生物活性

情報 PF-04691502は、ATP競争的PI3K/mTOR</b> 二重阻害剤で、IC50 が 32 nMです。
目標 PI3Kα PI3Kβ PI3Kδ PI3Kγ mTOR Akt
IC50 1.8 nM (Ki) 2.1 nM (Ki) 1.6 nM (Ki) 1.9 nM (Ki) 16 nM (Ki) 7.5 nM/3.8 nM [1]
In vitro試験 PF-04691502 potently inhibits recombinant class I PI3K and mTOR in biochemical assays and suppresses transformation of avian fibroblasts mediated by wild-type PI3K γ, δ, or mutant PI3Kα. In PIK3CA-mutant and PTEN-deleted cancer cell lines, PF-04691502 reduces phosphorylation of AKT T308 and AKT S473 (IC(50) of 7.5-47 nM and 3.8-20 nM, respectively) and inhibits cell proliferation (IC(50) of 179-313 nM). PF-04691502 inhibits mTORC1 activity in cells as measured by PI3K-independent nutrient stimulated assay, with an IC(50) of 32 nM and inhibits the activation of PI3K and mTOR downstream effectors including AKT, FKHRL1, PRAS40, p70S6K, 4EBP1, and S6RP. Short-term exposure to PF-04691502 predominantly inhibits PI3K, whereas mTOR inhibition persists for 24 to 48 hours. PF-04691502 induces cell cycle G(1) arrest, concomitant with upregulation of p27 Kip1 and reduction of Rb. [1]
In vivo試験 Antitumor activity of PF-04691502 is observed in U87 (PTEN null), SKOV3 (PIK3CA mutation), and gefitinib- and erlotinib-resistant non-small cell lung carcinoma xenografts. [1] PF-04691502 inhibits tumor growth at 7 days by 72%. FDG-PET imaging revealed that PF-04691502 reduces glucose metabolism dramatically. Tissue biomarkers of PI3K/mTOR pathway activity, p-AKT (S473), and p-RPS6 (S240/244), are also dramatically inhibited following PF-04691502 treatment. [2]
臨床試験 PF-04691502 is currently in Phase II clinical trials in patients with recurrent endometrial cancer and Breast Cancer. A Phase II clinical trials in patients with solid tumors has been completed.
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]

Kinase Assay The fluorescence polarization assay for ATP competitive inhibition is done as follows: mPI3Kα dilution solution (90 nM) is prepared in fresh assay buffer (50 mM Hepes pH 7.4, 150 mM NaCl, 5 mM DTT, 0.05% CHAPS) and kept on ice. The enzyme reaction contains 0.5 nM mouse PI3Kα (p110α/p85α complex purified from insect cells), 30 μM PIP2, PF-04691502 (0, 1, 4, and 8 nM), 5 mM MgCl2, and 2-fold serial dilutions of ATP (0–800 μM). Final dimethyl sulfoxide is 2.5%. The reaction is initiated by the addition of ATP and terminated after 30 minutes with 10 mM EDTA. In a detection plate, 15 uL of detector/probe mixture containing 480 nM GST-Grp1PH domain and 12 nM TAMRA tagged fluorescent PIP3 in assay buffer is mixed with 15 uL of kinase reaction mixture. The plate is shaken for 3 minutes, and incubated for 35 to 40 minutes before reading on an LJL Analyst HT.

細胞アッセイ: [1]

細胞系 BT20, U87MG, and SKOV3 cells
濃度 0-3 mM
処理時間 3 days
方法 BT20, U87MG, and SKOV3 cells are plated at 3,000 cell/well in 96-well culture plates in growth medium with 10% FBS. Cells are incubated overnight and treated with DMSO (0.1% final) or serial diluted compound for 3 days. Resazurin is added to 0.1 mg/mL. Plates are incubated at 37 °C in 5% CO2 for 3 hours. Fluorescence signals are read as emission at 590 nm after excitation at 530 nm. IC50 values are calculated by plotting fluorescence intensity to drug concentration in nonlinear curve

動物実験: [2]

動物モデル LSL-KrasG12D heterozygous mice (B6.129-Kras tm4Tyj) and Ptendel mice (c;129S4-Pten tm1Hwu/J), Orthotopic transplant of ovarian tumors
製剤 0.5% methylcellulose
投薬量 daily at either 7.5 or 10 mg/kg
管理 Administered via oral gavage

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 PF-04691502 SDF
分子量 425.48
化学式

C22H27N5O4

CAS No. 1013101-36-4
保管 2年-20℃
6月-80℃in DMSO
別名
溶解度 (25°C) * In vitro DMSO 14 mg/mL (32.9 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 2-amino-8-((1r,4r)-4-(2-hydroxyethoxy)cyclohexyl)-6-(6-methoxypyridin-3-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one

研究分野

カスタマーレビュー (1)


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Rating
Source Dr. Zhang of Tianjin Medical University. PF-04691502 purchased from Selleck
Method Western Blot
Cell Lines A549 cells
Concentrations 0-10 μM
Incubation Time 3 h
Results PF-04691502 treatment resulted in a reduction of AKT phosphorylation.

製品表彰状 (8)

技術サポート&よくある質問(FAQ)

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