PF-04691502 化学構造
分子量: 425.48

高品質保証

カスタマーフィードバック(3)

Quality Control & MSDS

製品説明

  • Compare PI3K Inhibitors
    PI3K製品生物活性の比較
  • 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

製品説明 PF-04691502は、ATP競争的PI3K/mTOR</b> 二重阻害剤で、IC50 が 32 nMです。
ターゲット 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

プロトコル (参考用のみ)

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]

細胞株 BT20, U87MG, and SKOV3 cells
濃度 0-3 mM
反応時間 3 days
実験の流れ 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
投与方法 Administered via oral gavage

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 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 solvent
別名 N/A
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

カスタマーフィードバック (3)


Click to enlarge
Rating
Source Mol Cancer Res, 2014, 12(10), 1520-31. PF-04691502 purchased from Selleck
Method Western blot
Cell Lines BMDMs
Concentrations 500 nM
Incubation Time 4 h
Results The other inhibitors used in early-phase clinical trials include: PI-103, a dual PI3K/mTOR inhibitor; PF4691502, a pan-PI3K inhibitor; and BKM120, a pan-PI3K inhibitor. The results shown in Figure clearly demonstrate that SF1126, PI-103, PF4691502, and BKM120 potently inhibit the hypoxic induction of HIF1α and HIF2α in BMDMs.

Click to enlarge
Rating
Source Toxicol Lett, 2013, 220(2), 150-6. PF-04691502 purchased from Selleck
Method Western blotting analysis
Cell Lines Hepatoma cells
Concentrations 0-20 uM
Incubation Time
Results As shown in Figure, incubation with PF-04691502 significantly reduced the amount of phosphorylated Akt (p-AktS473), whereas no change in total Akt levels was observed showing that PF-04691502 has no effect on total Akt protein expression. The tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) negatively regulates the PI3K pathway by dephosphorylating PIP3 to PIP2. Therefore, the expression of PTEN was also detected in PF-04691502-treated hepatoma cells. PF-04691502 was shown to upregulate the PTEN expression both in HepG2 cells and in Bel7402 cells.

Click to enlarge
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.

文献中の引用 (12)

技術サポート&よくある質問(FAQ)

ストックの作り方、阻害剤の保管する方法、細胞実験や動物実験に注意すべきな点を全部含めており、製品を取扱う時よくあった質問に対して取扱説明書でお答えいたします。

電話番号: +1-832-582-8158 Ext:3月曜日〜金曜日 9:00 AM–5:00 PM (米国中部標準時)

他の質問がある場合は、お気軽くお問合せください。

* 必須

Related PI3K 阻害剤

  • PI-3065

    PI-3065 is a selective p110δ inhibitor with IC50 of 15 nM, >70-fold selectivity over other PI3K family members.

  • GNE-317

    GNE-317 is a potent, brain-penetrant PI3K inhibitor.

  • Pilaralisib (XL147)

    Pilaralisib (XL147) is a selective and reversible class I PI3K inhibitor for PI3Kα/δ/γ with IC50 of 39 nM/36 nM/23 nM in cell-free assays, less potent to PI3Kβ. Phase 1/2.

  • LY2090314

    LY2090314 は GSK-3α と GSK-3βのために、強力なGSK-3阻害剤で、IC50 がそれぞれ1.5 nM と 0.9 nMです。

  • LY294002

    LY294002は、p110α、p110δとp110βのPI3K阻害剤で、IC50 がそれぞれ 0.5 μM、0.57 μM、0.97 μMです。

  • 3-Methyladenine (3-MA)

    3-Methyladenine (3-MA) は選択の自噬とリン酸イノシトール3キナーゼ(キナーゼ)阻害剤、Vps34 と PI3Kγ に作用する時、 IC50 がそれぞれ 25 nM と 60 nM になる。自動食物胞の形成を妨害すること。

  • BEZ235 (NVP-BEZ235, Dactolisib)

    BEZ235 (NVP-BEZ235, Dactolisib)は競争性的なPI3K、mTOR 阻害剤、 p110α, p110γ, p110δ と p110β を作用すると、 IC50 がぞれぞれ 4 nM, 5 nM, 7 nM と 75 nMになる.

  • Wortmannin

    ワートマニンはミオシン軽鎖キナーゼ(MLCK)のマルチターゲットの阻害剤、IC50がぞれぞれ0.17μMと3nMになる。自動食物胞の形成を妨害すること。

  • Pictilisib (GDC-0941)

    Pictilisib (GDC-0941)は、PI3Kα、PI3Kβ、PI3KδとPI3Kγの強力な阻害剤で、IC50 がそれぞれ 3 nM、 33 nM、 3 nM、75 nMです。

  • BKM120 (NVP-BKM120, Buparlisib)

    BKM120 (NVP-BKM120, Buparlisib)は、p110α、p110β、p110δとp110γの選択的なPI3K阻害剤で、IC50 がそれぞれ 52-99 nM、166 nM、 116 nM、 262 nMです。

最近チェックしたアイテム

Tags: PF-04691502を買う | PF-04691502供給者 | PF-04691502を購入する | PF-04691502費用 | PF-04691502生産者 | オーダーPF-04691502 | PF-04691502代理店
×
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description
お問い合わせ