PF-04691502 is a potent and selective inhibitor ofPI3KandmTOR. PF-04691502 binds to humanPI3Kα, β, δ, γ andmTORwithK_is of 1.8, 2.1, 1.6, 1.9 and 16 nM, respectively.

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 IC₅₀values 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 IC₅₀of 32 nM. PF-04691502 inhibits cell proliferation of BT20, SKOV3, and U87MG with IC₅₀values 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 (IC₅₀of 7.5-47 nM and 3.8-20 nM, respectively) and inhibits cell proliferation (IC₅₀of 179-313 nM). PF-04691502 inhibits mTORC1 activity in cells as measured by PI3K-independent nutrient stimulated assay, with an IC₅₀of 32 nM and inhibits the activation of PI3K and mTOR downstream effectors including AKT, FKHRL1, PRAS40, p70S6K, 4EBP1, and S6RP^[1].

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^[1].

425.48

Solid

C₂₂H₂₇N₅O₄

1013101-36-4

Room temperature in continental US; may vary elsewhere.

DMSO : 50 mg/mL(117.51 mM;Need ultrasonic)

请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。
储备液的保存方式和期限：-80℃, 6 months; -20℃, 1 month。-80℃ 储存时，请在 6 个月内使用，-20℃ 储存时，请在 1 个月内使用。

请根据您的实验动物和给药方式选择适当的溶解方案。以下溶解方案都请先按照In Vitro方式配制澄清的储备液，再依次添加助溶剂：

——为保证实验结果的可靠性，澄清的储备液可以根据储存条件，适当保存；体内实验的工作液，建议您现用现配，当天使用； 以下溶剂前显示的百
分比是指该溶剂在您配制终溶液中的体积占比；如在配制过程中出现沉淀、析出现象，可以通过加热和/或超声的方式助溶

• 1.

  请依序添加每种溶剂： 10% DMSO    40%PEG300   5%Tween-80   45% saline

  Solubility: ≥ 2.5 mg/mL (5.88 mM); Clear solution

  此方案可获得 ≥ 2.5 mg/mL (5.88 mM，饱和度未知) 的澄清溶液。

  以 1 mL 工作液为例，取 100 μL 25.0 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀；向上述体系中加入50 μL Tween-80，混合均匀；然后继续加入 450 μL生理盐水定容至 1 mL。

  将 0.9 g 氯化钠，完全溶解于 100 mL ddH2O 中，得到澄清透明的生理盐水溶液
• 2.

  请依序添加每种溶剂： 10% DMSO    90% (20%SBE-β-CDin saline)

  Solubility: ≥ 2.5 mg/mL (5.88 mM); Clear solution

  此方案可获得 ≥ 2.5 mg/mL (5.88 mM，饱和度未知) 的澄清溶液。

  以 1 mL 工作液为例，取 100 μL 25.0 mg/mL 的澄清 DMSO 储备液加到 900 μL20% 的 SBE-β-CD 生理盐水水溶液中，混合均匀。

  将 2 g 磺丁基醚 β-环糊精加入 5 mL 生理盐水中，再用生理盐水定容至 10 mL，完全溶解，澄清透明
• 3.

  请依序添加每种溶剂： 10% DMSO    90%corn oil

  Solubility: ≥ 2.5 mg/mL (5.88 mM); Clear solution

  此方案可获得 ≥ 2.5 mg/mL (5.88 mM，饱和度未知) 的澄清溶液，此方案不适用于实验周期在半个月以上的实验。

  以 1 mL 工作液为例，取 100 μL 25.0 mg/mL 的澄清 DMSO 储备液加到 900 μL玉米油中，混合均匀。