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
Cell Experiment | |
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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 | |
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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 |
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 Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 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 Compound A of 10 mg/kg.
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