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PF-04691502

CAS No. : 1013101-36-4

MCE 站：PF-04691502

产品活性：PF-04691502是有效和选择性的 PI3K 和 mTOR 的抑制剂。 PF-04691502与人PI3Kα，β，δ，γ和mTOR结合的 K_i 分别为1.8，2.1，1.6，1.9和16 nM。

研究领域：PI3K/Akt/mTOR  |  Autophagy

作用靶点：PI3K  |  mTOR  |  Autophagy

In Vitro: PF-04691502 inhibits recombinant mouse PI3Kα in an ATP-competitive inhibitor. PF-04691502 potently inhibits AKT phosphorylation on S473 ａnd T308 in all the 3 cancer cell lines with IC₅₀ values of 3.8 to 20 nM ａnd 7.5 to 47 nM, respectively. Using a 96-well plate-based P-S6RP(S235/236) ELISA assay, PF-04691502 potently inhibits mTORC1 activity with an IC₅₀ of 32 nM. PF-04691502 inhibits cell proliferation of BT20, SKOV3, ａnd U87MG with IC₅₀ values of 313, 188, ａnd 179 nM, respectively. In PIK3CA-mutant ａnd PTEN-deleted cancer cell lines, PF-04691502 reduces phosphorylation of AKT T308 ａnd AKT S473 (IC₅₀ of 7.5-47 nM ａnd 3.8-20 nM, respectively) ａnd inhibits cell proliferation (IC₅₀ of 179-313 nM). PF-04691502 inhibits mTORC1 activity in cells as measured by PI3K-independent nutrient stimulated assay, with an IC₅₀ of 32 nM ａnd inhibits the activation of PI3K ａnd mTOR downstream effectors including AKT, FKHRL1, PRAS40, p70S6K, 4EBP1, ａnd S6RP.

In Vivo: Nude mice bearing U87MG tumors are administered orally once a day with PF-04691502 at 0.5, 1, 5, ａnd 10 mg/kg (maximum tolerated dose, MTD). Treatment with 10 mg/kg results in a significant reduction of P-AKT(S473) levels at 1 hour postdosing, ａnd persistent inhibition is observed for 8 hours. P-AKT(S473) recovers to above baseline 24 hours after 10 mg/kg treatment. For P-S6RP(S235/236), a similar inhibition time course is observed, but after 24 hours of treatment, P-S6RP levels remain lower than vehicle tumors. Modulation of the AKT downstream effector, P-PRAS40(T246), ａnd mTOR downstream effector, P-4EBP1(T37/46), is observed. The PF-04691502-treated tumors are also evaluated by immunohistochemistry for levels of P-AKT(S473), total AKT, P-S6RP, ａnd total S6RP. Phosphorylation of AKT ａnd S6RP are significantly reduced at 4 hours after a single dose of PF-04691502 at 10 mg/kg. Dose-dependent tumor growth inhibition (TGI) is obtained in the U87MG xenograft model ａnd approximately 73% TGI is observed at the MTD dose of 10 mg/kg.

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