PF-04691502

Licensed by Pfizer Catalog No.S2743 Synonyms: PF4691502

PF-04691502 Chemical Structure

Molecular Weight(MW): 425.48

PF-04691502 is an ATP-competitive PI3K(α/β/δ/γ)/mTOR dual inhibitor with Ki of 1.8 nM/2.1 nM/1.6 nM/1.9 nM and 16 nM in cell-free assays, little activity against either Vps34, AKT, PDK1, p70S6K, MEK, ERK, p38, or JNK. Phase 2.

Size Price Stock Quantity  
In DMSO USD 190 In stock
USD 110 In stock
USD 170 In stock
USD 570 In stock
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3 Customer Reviews

  • BMDMs from WT animals were treated with different concentrations of PI3K inhibitors (500 nmol/L PF4691502, PI-103, BKM120 and 25 μmol/L SF1126) followed by hypoxia for 4 hours for Western blots. These macrophages were either used for lysate preparation (nuclear extracts for HIFα or WCE for pAKT and AKT) and Western blot analysis.

    Mol Cancer Res 2014 12(10), 1520-31. PF-04691502 purchased from Selleck.

    Western blotting analysis demonstrating p-Akt and PTEN levels in hepatoma cells. Cells were treated with the increasing concentrations of PF-04691502 for 24 h. The expression of Akt, p-Akt, and PTEN protein were assessed by western blotting analysis in HepG2 cells and Bel7402 cells. β-Actin was used as an internal standard.

    Toxicol Lett 2013 220(2), 150-6. PF-04691502 purchased from Selleck.

  • After starved in serum-free medium for 24h,A549 cells incubated with the indicated concentrations of PF-04691502 for 3h,followed by 20-minute stimolation of 100ng/ml EGF.

    Dr. Zhang of Tianjin Medical University. PF-04691502 purchased from Selleck.

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Biological Activity

Description PF-04691502 is an ATP-competitive PI3K(α/β/δ/γ)/mTOR dual inhibitor with Ki of 1.8 nM/2.1 nM/1.6 nM/1.9 nM and 16 nM in cell-free assays, little activity against either Vps34, AKT, PDK1, p70S6K, MEK, ERK, p38, or JNK. Phase 2.
Targets
PI3Kδ [1]
(Cell-free assay)
PI3Kα [1]
(Cell-free assay)
PI3Kγ [1]
(Cell-free assay)
PI3Kβ [1]
(Cell-free assay)
P-Akt (S473) [1]
(Cell-free assay)
1.6 nM(Ki) 1.8 nM(Ki) 1.9 nM(Ki) 2.1 nM(Ki) 3.8 nM
In vitro

PF-04691502 potently inhibits recombinant class I PI3K and mTOR in biochemical assays and suppresses transformation of avian fibroblasts mediated by wild-type PI3K γ, δ, or mutant PI3Kα. In PIK3CA-mutant and PTEN-deleted cancer cell lines, PF-04691502 reduces phosphorylation of AKT T308 and AKT S473 (IC(50) of 7.5-47 nM and 3.8-20 nM, respectively) and inhibits cell proliferation (IC(50) of 179-313 nM). PF-04691502 inhibits mTORC1 activity in cells as measured by PI3K-independent nutrient stimulated assay, with an IC(50) of 32 nM and inhibits the activation of PI3K and mTOR downstream effectors including AKT, FKHRL1, PRAS40, p70S6K, 4EBP1, and S6RP. Short-term exposure to PF-04691502 predominantly inhibits PI3K, whereas mTOR inhibition persists for 24 to 48 hours. PF-04691502 induces cell cycle G(1) arrest, concomitant with upregulation of p27 Kip1 and reduction of Rb. [1]

In vivo Antitumor activity of PF-04691502 is observed in U87 (PTEN null), SKOV3 (PIK3CA mutation), and gefitinib- and erlotinib-resistant non-small cell lung carcinoma xenografts. [1] PF-04691502 inhibits tumor growth at 7 days by 72%. FDG-PET imaging revealed that PF-04691502 reduces glucose metabolism dramatically. Tissue biomarkers of PI3K/mTOR pathway activity, p-AKT (S473), and p-RPS6 (S240/244), are also dramatically inhibited following PF-04691502 treatment. [2]

Protocol

Kinase Assay:[1]
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Kinase Assay:

The fluorescence polarization assay for ATP competitive inhibition is done as follows: mPI3Kα dilution solution (90 nM) is prepared in fresh assay buffer (50 mM Hepes pH 7.4, 150 mM NaCl, 5 mM DTT, 0.05% CHAPS) and kept on ice. The enzyme reaction contains 0.5 nM mouse PI3Kα (p110α/p85α complex purified from insect cells), 30 μM PIP2, PF-04691502 (0, 1, 4, and 8 nM), 5 mM MgCl2, and 2-fold serial dilutions of ATP (0–800 μM). Final dimethyl sulfoxide is 2.5%. The reaction is initiated by the addition of ATP and terminated after 30 minutes with 10 mM EDTA. In a detection plate, 15 uL of detector/probe mixture containing 480 nM GST-Grp1PH domain and 12 nM TAMRA tagged fluorescent PIP3 in assay buffer is mixed with 15 uL of kinase reaction mixture. The plate is shaken for 3 minutes, and incubated for 35 to 40 minutes before reading on an LJL Analyst HT.
Cell Research:[1]
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  • Cell lines: BT20, U87MG, and SKOV3 cells
  • Concentrations: 0-3 mM
  • Incubation Time: 3 days
  • Method: BT20, U87MG, and SKOV3 cells are plated at 3,000 cell/well in 96-well culture plates in growth medium with 10% FBS. Cells are incubated overnight and treated with DMSO (0.1% final) or serial diluted compound for 3 days. Resazurin is added to 0.1 mg/mL. Plates are incubated at 37 °C in 5% CO2 for 3 hours. Fluorescence signals are read as emission at 590 nm after excitation at 530 nm. IC50 values are calculated by plotting fluorescence intensity to drug concentration in nonlinear curve
    (Only for Reference)
Animal Research:[2]
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  • Animal Models: LSL-KrasG12D heterozygous mice (B6.129-Kras tm4Tyj) and Ptendel mice (c;129S4-Pten tm1Hwu/J), Orthotopic transplant of ovarian tumors
  • Formulation: 0.5% methylcellulose
  • Dosages: daily at either 7.5 or 10 mg/kg
  • Administration: Administered via oral gavage
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 14 mg/mL (32.9 mM)
Water <1 mg/mL
Ethanol <1 mg/mL
In vivo

* 1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Information

Molecular Weight 425.48
Formula

C22H27N5O4

CAS No. 1013101-36-4
Storage powder
in solvent
Synonyms PF4691502

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Clinical Trial Information

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT01658176 Withdrawn Breast Neoplasms Pfizer January 2013 Phase 2
NCT01430585 Terminated Early Breast Cancer (Phase 2)|Advanced Breast Cancer (Phase 1b) Pfizer March 2012 Phase 2
NCT00927823 Completed Cancer Pfizer December 2009 Phase 1

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Handling Instructions

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID