PF-04691502 Licensed by Pfizer

Catalog No.S2743

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.

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PF-04691502 Chemical Structure

PF-04691502 Chemical Structure
Molecular Weight: 425.48

Validation & Quality Control

Customer Product Validation(3)

Quality Control & MSDS

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PF-04691502 is available in the following compound libraries:

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Product Description

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)

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IC50 1.6 nM(Ki) 1.8 nM(Ki) 1.9 nM(Ki) 2.1 nM(Ki)
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]
Features

Protocol(Only for 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
Formulation 0.5% methylcellulose
Dosages daily at either 7.5 or 10 mg/kg
Administration Administered via oral gavage

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 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 resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Yuan J, Mol Cancer Ther, 2011, 10(11), 2189-2199

[2] Kinross KM, Mol Cancer Ther, 2011, 10(8), 1440-1449

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Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-05-07)

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

Chemical Information

Download PF-04691502 SDF
Molecular Weight (MW) 425.48
Formula

C22H27N5O4

CAS No. 1013101-36-4
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms PF4691502
Solubility (25°C) * In vitro DMSO 14 mg/mL (32.9 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
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 Name 2-amino-8-((1r,4r)-4-(2-hydroxyethoxy)cyclohexyl)-6-(6-methoxypyridin-3-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one

Customer Product Validation (3)


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Rating
Source Mol Cancer Res 2014 12(10), 1520-31. PF-04691502 purchased from Selleck
Method Western blot
Cell Lines BMDMs
Concentrations 500 nM
Incubation Time 4 h
Results The other inhibitors used in early-phase clinical trials include: PI-103, a dual PI3K/mTOR inhibitor; PF4691502, a pan-PI3K inhibitor; and BKM120, a pan-PI3K inhibitor. The results shown in Figure clearly demonstrate that SF1126, PI-103, PF4691502, and BKM120 potently inhibit the hypoxic induction of HIF1α and HIF2α in BMDMs.

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Rating
Source Toxicol Lett 2013 220(2), 150-6. PF-04691502 purchased from Selleck
Method Western blotting analysis
Cell Lines Hepatoma cells
Concentrations 0-20 uM
Incubation Time
Results As shown in Figure, incubation with PF-04691502 significantly reduced the amount of phosphorylated Akt (p-AktS473), whereas no change in total Akt levels was observed showing that PF-04691502 has no effect on total Akt protein expression. The tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) negatively regulates the PI3K pathway by dephosphorylating PIP3 to PIP2. Therefore, the expression of PTEN was also detected in PF-04691502-treated hepatoma cells. PF-04691502 was shown to upregulate the PTEN expression both in HepG2 cells and in Bel7402 cells.

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Rating
Source Dr. Zhang of Tianjin Medical University. PF-04691502 purchased from Selleck
Method Western Blot
Cell Lines A549 cells
Concentrations 0-10 μM
Incubation Time 3 h
Results PF-04691502 treatment resulted in a reduction of AKT phosphorylation.

Tech Support

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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