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Purity: ≥98%
PF-04691502 is a novel, potent, ATP-competitive and selective dual inhibitor of PI3K (phosphatidylinositol 3 kinase) and mTOR (mammalian target of rapamycin) with potential anticancer activity. With Ki of 1.8 nM, 2.1 nM, 1.6 nM, 1.9 nM, and 16 nM in cell-free assays, it inhibits PI3K(α/β/δ/γ)/mTOR. In terms of Vps34, AKT, PDK1, p70S6K, MEK, ERK, p38, or JNK, PF04691502 exhibits little activity. When cancer cells overexpress PI3K/mTOR, the potential anticancer drug PF-04691502 inhibits tumor growth.
Targets |
PI3Kδ (Ki = 1.6 nM); PI3Kα (Ki = 1.8 nM); PI3Kγ (Ki = 1.9 nM); PI3Kβ (Ki = 2.1 nM); mTOR (Ki = 16 nM)
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ln Vitro |
PF-04691502 inhibits recombinant class I PI3K and mTOR in biochemical assays and prevents the transformation of avian fibroblasts caused by wild-type PI3K γ, δ, or mutant PI3Kα.
PF-04691502 inhibits cell proliferation (IC(50) of 179-313 nM) and lowers phosphorylation of AKT T308 and AKT S473 in PIK3CA-mutant and PTEN-deleted cancer cell lines, respectively. With an IC(50) of 32 nM, PF-04691502 inhibits the activity of mTORC1 in cells as determined by the PI3K-independent nutrient stimulated assay. It also prevents the activation of PI3K and mTOR downstream effectors such as AKT, FKHRL1, PRAS40, p70S6K, 4EBP1, and S6RP. While mTOR inhibition lasts for 24 to 48 hours after exposure to PF-04691502, short-term exposure primarily inhibits PI3K. In addition to upregulating p27 Kip1 and downregulating Rb, PF-04691502 causes cell cycle G(1) arrest. [1]
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ln Vivo |
In SKOV3 (PIK3CA mutation), U87 (PTEN null), and gefitinib- and erlotinib-resistant non-small cell lung carcinoma xenografts, antitumor activity of PF-04691502 is seen. [1] At 7 days, PF-04691502 reduces tumor growth by 72%. FDG-PET imaging demonstrated that PF-04691502 significantly lowers glucose metabolism. Following PF-04691502 treatment, p-AKT (S473) and p-RPS6 (S240/244), two tissue biomarkers of PI3K/mTOR pathway activity, are also severely inhibited. [2]
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Enzyme Assay |
The following procedure is used for the ATP competitive inhibition fluorescence polarization assay: 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). Dimethyl sulfoxide is 2.5% in the finished product. ATP is used to start the reaction, and 10 mM EDTA is used to stop it after 30 minutes. In a detection plate, 15 uL of the kinase reaction mixture is combined with 15 uL of the detector/probe mixture, which contains 480 nM GST-Grp1PH domain and 12 nM TAMRA-tagged fluorescent PIP3 in assay buffer. Before the plate is read on an LJL Analyst HT, it is shaken for 3 minutes and incubated for 35 to 40 minutes.
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Cell Assay |
In 96-well culture plates with growth medium containing 10% FBS, BT20, U87MG, and SKOV3 cells are seeded at a density of 3,000 cells per well. DMSO (0.1% final) or a compound that has been serially diluted is applied to cells after an overnight incubation period. 0.1 mg/mL receives resazurin addition. For three hours, plates are incubated in 5% CO2 at 37 °C. Following excitation at 530 nm, fluorescence signals are read as emission at 590 nm. Fluorescence intensity and drug concentration are plotted on a nonlinear curve to determine the IC50 values.
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Animal Protocol |
Mice: Female nu/nu mice (6-8 weeks old) are used. To prepare for implantation, tumor cells are removed and then re-suspended in matrigel (1:1) and serum-free medium. The region of the back flank is subcutaneously implanted with SKOV3, U87MG, or NSCLC cells (2.5-4 106). When a tumor's size ranges from 100 to 200 mm3, treatment can begin. The daily oral administration of PF-04691502 contains 0.5% methylcellulose in water suspension. Every two to three days, tumor volumes and animal body weights are measured. Vernier calipers are used to measure and calculate tumor volume. Calculated tumor growth inhibition (TGI) percentage. Data are shown as mean±SE.
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References |
Molecular Formula |
C22H27N5O4
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Molecular Weight |
425.48
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Exact Mass |
425.2063
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Elemental Analysis |
C, 62.10; H, 6.40; N, 16.46; O, 15.04
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CAS # |
1013101-36-4
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Appearance |
Solid powder
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SMILES |
CC1=C2C=C(C(=O)N(C2=NC(=N1)N)C3CCC(CC3)OCCO)C4=CN=C(C=C4)OC
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InChi Key |
XDLYKKIQACFMJG-UHFFFAOYSA-N
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InChi Code |
InChI=1S/C22H27N5O4/c1-13-17-11-18(14-3-8-19(30-2)24-12-14)21(29)27(20(17)26-22(23)25-13)15-4-6-16(7-5-15)31-10-9-28/h3,8,11-12,15-16,28H,4-7,9-10H2,1-2H3,(H2,23,25,26)
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Chemical Name |
2-amino-8-[4-(2-hydroxyethoxy)cyclohexyl]-6-(6-methoxypyridin-3-yl)-4-methylpyrido[2,3-d]pyrimidin-7-one
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Synonyms |
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HS Tariff Code |
2934.99.9001
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Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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Solubility (In Vitro) |
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Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
1 mM | 2.3503 mL | 11.7514 mL | 23.5029 mL | |
5 mM | 0.4701 mL | 2.3503 mL | 4.7006 mL | |
10 mM | 0.2350 mL | 1.1751 mL | 2.3503 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration: mg/mL;
Method for preparing DMSO stock solution: mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation::Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O,mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
NCT Number | Status | Interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
NCT00445315 | Completed | Drug: PF-00868554 Drug: Placebo |
Hepatitis C | Pfizer | January 2007 | Phase 1 |
NCT01658176 | Withdrawn | Drug: PF-04691502 Drug: Exemestane |
Breast Neoplasms | Pfizer | January 2013 | Phase 2 |
Kinross KM, Mol Cancer Ther, 2011, 10(8), 1440-1449 td> |