受注:045-509-1970 |
技術サポート:[email protected] 平日9:00〜18:00 1営業日以内にご連絡を差し上げます |
Synonyms | PF4691502 | Storage (From the date of receipt) |
3 years -20°C powder 1 years -80°C in solvent |
|
化学式 | C22H27N5O4 |
|||
分子量 | 425.48 | CAS No. | 1013101-36-4 | |
Solubility (25°C)* | 体外 | DMSO | 17 mg/mL (39.95 mM) | |
Ethanol | 7 mg/mL (16.45 mM) | |||
Water | Insoluble | |||
* <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. |
製品説明 | PF-04691502 (PF4691502) is an ATP-competitive PI3K(α/β/δ/γ)/mTOR dual inhibitor with Ki of 1.8 nM/2.1 nM/1.6 nM/1.9 nM and 16 nM in cell-free assays, little activity against either Vps34, AKT, PDK1, p70S6K, MEK, ERK, p38, or JNK. PF-04691502 induces apoptosis. Phase 2. |
---|---|
in vitro | 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 | 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] |
キナーゼアッセイ | 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 | 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 | 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 |
投薬量 | daily at either 7.5 or 10 mg/kg | |
投与方法 | Administered via oral gavage |
|
Data from [Data independently produced by Mol Cancer Res, 2014, 12(10), 1520-31]
Data from [Data independently produced by Toxicol Lett, 2013, 220(2), 150-6]
, , Dr. Zhang of Tianjin Medical University
Inhibitor PF-04691502 works as a senolytic to regulate cellular senescence [ Exp Gerontol, 2024, 186:112359] | PubMed: 38184267 |
Zebrafish functional xenograft vasculature platform identifies PF-502 as a durable vasculature normalization drug [ iScience, 2023, 26(9):107734] | PubMed: 37680473 |
Functional restoration of lysosomes and mitochondria through modulation of AKT activity ameliorates senescence [ Exp Gerontol, 2023, 173:112091] | PubMed: 36657533 |
Glucose metabolic upregulation via phosphorylation of S6 ribosomal protein affects tumor progression in distal cholangiocarcinoma [ BMC Gastroenterol, 2023, 23(1):157] | PubMed: 37193984 |
RNF43G659fs is an oncogenic colorectal cancer mutation and sensitizes tumor cells to PI3K/mTOR inhibition [ Nature Communications, 2022, 3181-2022)] | PubMed: None |
RNF43 G659fs is an oncogenic colorectal cancer mutation and sensitizes tumor cells to PI3K/mTOR inhibition [ Nat Commun, 2022, 13(1):3181] | PubMed: 35676246 |
A novel PI3K inhibitor XH30 suppresses orthotopic glioblastoma and brain metastasis in mice models [ Acta Pharm Sin B, 2022, 12(2):774-786] | PubMed: 35256946 |
A novel PI3K inhibitor XH30 suppresses orthotopic glioblastoma and brain metastasis in mice models [ Acta Pharm Sin B, 2022, 12(2):774-786] | PubMed: 35256946 |
Leveraging patient derived models of FGFR2 fusion positive intrahepatic cholangiocarcinoma to identify synergistic therapies [ NPJ Precis Oncol, 2022, 6(1):75] | PubMed: 36274097 |
Identification of New Vulnerabilities in Conjunctival Melanoma Using Image-Based High Content Drug Screening [ Cancers (Basel), 2022, 14(6)1575] | PubMed: 35326726 |
長期の保管のために-20°Cの下で製品を保ってください。
人間や獣医の診断であるか治療的な使用のためにでない。
各々の製品のための特定の保管と取扱い情報は、製品データシートの上で示されます。大部分のSelleck製品は、推薦された状況の下で安定です。製品は、推薦された保管温度と異なる温度で、時々出荷されます。長期の保管のために必要とされてそれと異なる温度で、多くの製品は、短期もので安定です。品質を維持するが、夜通しの積荷のために最も経済的な貯蔵状況を用いてあなたの送料を保存する状況の下に、製品が出荷されることを、我々は確実とします。製品の受領と同時に、製品データシートの上で貯蔵推薦に従ってください。