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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.
Mol Ther Nucleic Acids. 2016 Nov 15;5(11):e384.
Enhanced Anticancer Activity of PF-04691502, a Dual PI3K/mTOR Inhibitor, in Combination With VEGF siRNA Against Non–small-cell Lung Cancer
PF-04691502 purchased from AbMole
. pf-04691502, figure 7..jpg) |
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). |
. pf-04691502, figure 6..jpg) |
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). |
. pf-04691502, figure 5..jpg) |
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. |
. pf-04691502, figure 4..jpg) |
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. |
. pf-04691502, figure 3..jpg) |
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). |
. pf-04691502, figure 2..jpg) |
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. |
. pf-04691502, figure 1..jpg) |
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). |
| 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 |
| Molecular Weight | 425.48 |
| Formula | C22H27N5O4 |
| CAS Number | 1013101-36-4 |
| Solubility (25°C) | DMSO 13 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
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