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PF-04691502

Cat. No. M1984
PF-04691502 Structure
Size Price Availability Quantity
10mg USD 120 In stock
50mg USD 450 In stock
100mg USD 770 In stock
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Quality Control
Biological Activity

PF-04691502 is an ATP-competitive PI3K/mTOR dual inhibitor, which potently inhibited recombinant class I PI3K and mTOR in biochemical assays and suppressed transformation of avian fibroblasts mediated by wild-type PI3K γ, δ, or mutant PI3Kα. PF-04691502 inhibited mTORC1 activity in cells as measured by PI3K-independent nutrient stimulated assay, with an IC(50) of 32 nmol/L and inhibited the activation of PI3K and mTOR downstream effectors including AKT, FKHRL1, PRAS40, p70S6K, 4EBP1, and S6RP. PF-04691502 reduced phosphorylation of AKT T308 and AKT S473 (IC(50) of 7.5-47 nmol/L and 3.8-20 nmol/L, respectively) and inhibited cell proliferation (IC(50) of 179-313 nmol/L) in PIK3CA-mutant and PTEN-deleted cancer cell lines. PF-04691502 induced cell cycle G(1) arrest, concomitant with upregulation of p27 Kip1 and reduction of Rb. PF-04691502 has entered phase II clinical trials.

Protocol
Cell Experiment
Cell lines BT20, U87MG, and SKOV3 cells
Preparation method Cell proliferation assays.
BT20, U87MG, and SKOV3 cells were plated at 3,000 cell/well in 96-well culture plates in growth medium with 10% FBS. Cells were incubated overnight and treated with DMSO (0.1% final) or serial diluted compound for 3 days. Resazurin was added to 0.1 mg/mL. Plates were incubated at 37°C in 5% CO2 for 3 hours. Fluorescence signals were read as emission at 590 nm after excitation at 530 nm. IC50 values were calculated by plotting fluorescence intensity to drug concentration in nonlinear curves.
Concentrations 0~1000 nM
Incubation time 3 days
Animal Experiment
Animal models SKOV3, U87MG, or NSCLC cells tumour xenograft models in Female nu/nu mice (6–8 weeks old)
Formulation 0.5% methylcellulose in water suspension
Dosages 0.5, 1, 5, and 10 mg/kg once daily
Administration orally
Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)
Species Mouse Rat Rabbit Guinea pig Hamster Dog
Weight (kg) 0.02 0.15 1.8 0.4 0.08 10
Body Surface Area (m2) 0.007 0.025 0.15 0.05 0.02 0.5
Km factor 3 6 12 8 5 20
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.

Chemical Information
Molecular Weight 425.48
Formula C22H27N5O4
CAS Number 1013101-36-4
Purity >99%
Solubility DMSO
Storage at -20°C
Customer Product Validations & Biological Datas
Source Mol Ther Nucleic Acids.(2016). PF-04691502, Figure 7. (Abmole Bioscience, Houston, TX)
Method
Cell Lines A549 and H460 cell
Concentrations 5 nmol/l to 5 µmol/l for A549, and 5 nmol/l to 100 µmol/l for H460 cells
Incubation Time 72 h
Results In A549 cells PF0 and siRNA-V combination revealed a moderate synergism at 6 and 12 nmol/l siRNA-V concentration, and slight synergism at 18 nmol/l, with CI values between 0.62 and 0.88 (Figure 7a, Table 1). In H460 cells, PF0 and siRNA-V showed moderate synergism at 4 nmol/l siRNA-V concentration, synergism at 6 nmol/l, and slight synergism at 12 nmol/l, with CI values between 0.51 and 0.81 (Figure 7b, Table 1).
Rating
Source Mol Ther Nucleic Acids.(2016). PF-04691502, Figure 6. (Abmole Bioscience, Houston, TX)
Method tube formation assays
Cell Lines human umbilical vein endothelial cells (HUVEC)
Concentrations 100 nmol/l
Incubation Time 6 h
Results PF0 treatment showed poor organization of HUVEC tube-like structures and a nonsignificant (P < 0.05) decrease in segments length (75.63 ± 13.71%) compared to control (Figure 6e).
Rating
Source Mol Ther Nucleic Acids.(2016). PF-04691502, Figure 5. (Abmole Bioscience, Houston, TX)
Method wound healing assay
Cell Lines A549 and H460 cell
Concentrations
Incubation Time
Results A549 and H460 cells also showed significant (P < 0.05) differences between PF0 (200 nmol/l for A549 and 2,000 nmol/l for H460) treated and nontreated cells (Figure 5c,d). A549 cells showed that after 16 hours of 50 nmol/l siRNA-V and 200 nmol/l PF0 treatment wound closure was 18.48 ± 1.60% comparing with 47.24 ± 2.09 of the control treated cells.
Rating
Source Mol Ther Nucleic Acids.(2016). PF-04691502, Figure 4. (Abmole Bioscience, Houston, TX)
Method Inhibition of anchorage-dependent colony formation
Cell Lines A549 and H460 cells
Concentrations 200 nmol/l for A549 and 2,000 nmol/l for H460
Incubation Time
Results The reduction was more remarkable after PF0 was combined with siRNA-V showing a significant (P < 0.05) decrease in colony formation to a 29.83 ± 8.11% as compared with control. For A549 cells, the combination resulted in a significant (P < 0.05) colony formation reduction when compared with PF0 treatment (Figure 4c). The relative colony-forming ability of H460 cells was reduced after PF0 treatment to 61.86 ± 20.48% and after siRNA-V treatment to 73.21 ± 1.97% as compared with controls (Figure 4b,d). PF0 and siRNA-V combination showed a significant (P < 0.05) decrease in relative colony formation to 7.97 ± 9.20% as compared with control groups.
Rating
Source Mol Ther Nucleic Acids.(2016). PF-04691502, Figure 3. (Abmole Bioscience, Houston, TX)
Method VEGF silencing effect analysis by quantitative real-time PCR
Cell Lines A549 and H460 cells
Concentrations 200 nmol/l for A549 and 2,000 nmol/l for H460
Incubation Time 48 h
Results In A549 cells, the siRNA-V treatment showed a significant (P < 0.05) decrease of 62.58 ± 16.60% in VEGF gene expression compared to control (Figure 3a). siRNAV and PF0 combination treatment showed a significantly (P < 0.01) decreased VEGF expression of 75.06 ± 13.21% compared to control. In H460 cells, we observed a significant (P < 0.001) decrease in the relative VEGF mRNA expression after siRNA-V transfection by 92.22 ± 3.10% as well as after the combination treatment 69.59 ± 7.71% compared to control cells (Figure 3b).
Rating
Source Mol Ther Nucleic Acids.(2016). PF-04691502, Figure 2. (Abmole Bioscience, Houston, TX)
Method siRNA-V and PF0 combination cytotoxicity assays
Cell Lines A549, H460 cells
Concentrations 5 to 500 nmol/l for A549, and 10 to 5,000 nmol/l for H460 cells
Incubation Time 24, 48, and 72 h
Results We observed a significant (P < 0.05) decrease in relative cell viability for the combination compared to singleagent treatments (Figure 2a,b). The combination cytotoxicity assays demonstrated that siRNA-V potentiates the anticancer activity of PF0 against A459 and H460 cells.
Rating
Source Mol Ther Nucleic Acids.(2016). PF-04691502, Figure 1. (Abmole Bioscience, Houston, TX)
Method Dose response cytotoxicity analysis
Cell Lines A549 cells
Concentrations 5 to 5,000 nmol/l
Incubation Time 24, 48, and 72 h
Results In H460 cells, PF0 (5 nmol/l to 200 µmol/l) or siRNA-V (5 to 200 nmol/l) cytotoxicity was also found to be dose and time dependent (Figure 1d,e and Supplementary Figure S2). IC50 values for PF0 in H460 cells were 1,965.5 ± 131.7 nmol/l; 1,080.1 ± 307.1 nmol/l; 936.7 ± 174.6 nmol/l after 24, 48, and 72 hours of treatment respectively (Figure 1d and Supplementary Figure S2a).
Rating
Product Citations
References

PF-04691502, a potent and selective oral inhibitor of PI3K and mTOR kinases with antitumor activity.
Yuan J, et al. Mol Cancer Ther. 2011 Nov;10(11):2189-99. PMID: 21750219.

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