PF-04691502

Catalog No.S2743 Batch:S274350

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Technical Data

Formula

C22H27N5O4
Molecular Weight 425.48 CAS No. 1013101-36-4
Solubility (25°C)* In vitro DMSO 85 mg/mL (199.77 mM)
Ethanol 3 mg/mL (7.05 mM)
Water Insoluble
In vivo (Add solvents to the product individually and in order)
Clear solution
5% DMSO 95% Corn oil
0.6mg/ml Taking the 1 mL working solution as an example, add 50 μL of 12 mg/ml clear DMSO stock solution to 950 μL of corn oil and mix evenly. The mixed solution should be used immediately for optimal results. 
Clear solution
5%DMSO 40%PEG300 5%Tween80 50%ddH2O
0.6mg/ml Taking the 1 mL working solution as an example, add 50 μL of 12 mg/ml clarified DMSO stock solution to 400 μL of PEG300, mix evenly to clarify it; add 50 μL of Tween80 to the above system, mix evenly to clarify; then continue to add 500 μL of ddH2O to adjust the volume to 1 mL. The mixed solution should be used immediately for optimal results. 
* <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.
* Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

Preparing Stock Solutions

Biological Activity

Description PF-04691502 (PF4691502) 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. PF-04691502 induces apoptosis. 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)		 View More
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 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 (from reference)

Kinase Assay:

[1]
  • 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 Assay:

[1]
  • 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
Animal Study:

[2]
  • Animal Models

    LSL-KrasG12D heterozygous mice (B6.129-Kras tm4Tyj) and Ptendel mice (c;129S4-Pten tm1Hwu/J), Orthotopic transplant of ovarian tumors

  • Dosages

    daily at either 7.5 or 10 mg/kg

  • Administration

    Administered via oral gavage

Customer Product Validation

Data from [Data independently produced by Mol Cancer Res, 2014, 12(10), 1520-31]

Data from [Data independently produced by Toxicol Lett, 2013, 220(2), 150-6]

, , Dr. Zhang of Tianjin Medical University

Data from [Data independently produced by , , Onco Targets Ther, 2018, 11:943-953]

Selleck's PF-04691502 has been cited by 50 publications

Inhibitor PF-04691502 works as a senolytic to regulate cellular senescence [ Exp Gerontol, 2024, 186:112359] PubMed: 38184267
Zebrafish functional xenograft vasculature platform identifies PF-502 as a durable vasculature normalization drug [ iScience, 2023, 26(9):107734] PubMed: 37680473
Functional restoration of lysosomes and mitochondria through modulation of AKT activity ameliorates senescence [ Exp Gerontol, 2023, 173:112091] PubMed: 36657533
Glucose metabolic upregulation via phosphorylation of S6 ribosomal protein affects tumor progression in distal cholangiocarcinoma [ BMC Gastroenterol, 2023, 23(1):157] PubMed: 37193984
RNF43G659fs is an oncogenic colorectal cancer mutation and sensitizes tumor cells to PI3K/mTOR inhibition [ Nature Communications, 2022, 3181-2022)] PubMed: None
RNF43 G659fs is an oncogenic colorectal cancer mutation and sensitizes tumor cells to PI3K/mTOR inhibition [ Nat Commun, 2022, 13(1):3181] PubMed: 35676246
A novel PI3K inhibitor XH30 suppresses orthotopic glioblastoma and brain metastasis in mice models [ Acta Pharm Sin B, 2022, 12(2):774-786] PubMed: 35256946
A novel PI3K inhibitor XH30 suppresses orthotopic glioblastoma and brain metastasis in mice models [ Acta Pharm Sin B, 2022, 12(2):774-786] PubMed: 35256946
Leveraging patient derived models of FGFR2 fusion positive intrahepatic cholangiocarcinoma to identify synergistic therapies [ NPJ Precis Oncol, 2022, 6(1):75] PubMed: 36274097
Identification of New Vulnerabilities in Conjunctival Melanoma Using Image-Based High Content Drug Screening [ Cancers (Basel), 2022, 14(6)1575] PubMed: 35326726

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SHIPPING AND STORAGE
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