Dacomitinib (PF299804, PF299)

Catalog No.S2727

Dacomitinib (PF299804, PF299) is a potent, irreversible pan-ErbB inhibitor, mostly to EGFR with IC50 of 6 nM in a cell-free assay, effective against NSCLCs with EGFR or ERBB2 mutations (resistant to gefitinib) as well as those harboring the EGFR T790M mutation. Phase 2.

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Dacomitinib (PF299804, PF299) Chemical Structure

Dacomitinib (PF299804, PF299) Chemical Structure
Molecular Weight: 469.94

Validation & Quality Control

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Quality Control & MSDS

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Product Information

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  • Research Area
  • Combination Therapy
    Combination Therapy

Product Description

Biological Activity

Description Dacomitinib (PF299804, PF299) is a potent, irreversible pan-ErbB inhibitor, mostly to EGFR with IC50 of 6 nM in a cell-free assay, effective against NSCLCs with EGFR or ERBB2 mutations (resistant to gefitinib) as well as those harboring the EGFR T790M mutation. Phase 2.
Targets EGFR [1]
(Cell-free assay)
ErbB2 [1]
(Cell-free assay)
ErbB4 [1]
(Cell-free assay)
IC50 6.0 nM 45.7 nM 73.7 nM
In vitro PF299804 is a specific inhibitor of the ERBB family of kinases. PF299804 inhibits EGFR signaling and induces apoptosis in the EGFR T790M-containing H3255 GR cell line. PF299804 is effective in gefitinib-sensitive and gefitinibresistant NSCLC cell lines. PF299804 inhibits the growth of H3255 and HCC827 cells engineered to express EGFR T790M. PF299804 inhibits EGFR phosphorylation in the presence of the T790M mutation. [1] PF-299804 is believed to irreversibly inhibit ERBB tyrosine kinase activity through binding at the ATP site and covalent modification of nucleophilic cysteine residues in the catalytic domains of ERBB family members. [2] PF299804 shows significant growth-inhibitory effects in HER2-amplified gastric cancer cells (SNU216, N87), and it has lower 50% inhibitory concentration values compared with other EGFR tyrosine kinase inhibitors, including gefitinib, lapatinib, BIBW-2992, and CI-1033. PF299804 induces apoptosis and G1 arrest and inhibits phosphorylation of receptors in the HER family and downstream signaling pathways including STAT3, AKT, and extracellular signal-regulated kinases (ERK) in HER2-amplified gastric cancer cells. PF299804 also blocks EGFR/HER2, HER2/HER3, and HER3/HER4 heterodimer formation as well as the association of HER3 with p85α in SNU216 cells. [3] A recent research uses forty-seven human breast cancer and immortalized breast epithelial lines to evaluate the inhibition effects of PF299804, the results indicate PF299804 preferentially inhibits growth of HER-2-amplified breast cancer cell lines than nonamplified lines (RR = 3.39, p < 0.0001). PF299804 reduces the phosphorylation of HER2, EGFR, HER4, AKT, and ERK in the majority of sensitive lines. PF299804 exerts its anti-proliferative effect through a combined G0/G1 arrest and an induction of apoptosis. [4]
In vivo Orally administered PF299804 effectively inhibits growth of HCC827 Del/T790M xenografts. [1] Low oral administration of PF-299804 (15mg/kg) causes significant antitumor activity, including marked tumor regressions in a variety of human tumor xenograft models that express and/ or overexpress ERBB family members or contain the double mutation (L858R/T790M) in ERBB1 (EGFR) associated with resistance to gefitinib and erlotinib. [2]
Features

Protocol(Only for Reference)

Kinase Assay: [1]

ELISA-Based ERBB Kinase Assay The ERBB1, ERBB 2, and ERBB4 cytoplasmic fusion proteins are made by cloning the ERBB1 sequence (Met-668 to Ala-1211), ERBB2 (Ile-675 to Val-1256), and ERBB4 sequence (Gly-259 to Gly-690) into the baculoviral vector pFastBac using PCR. Proteins are expressed in baculovirusinfected Sf9 insect cells as GST fusion proteins. The proteins are purified by affinity chromatography using glutathione sepharose beads. Inhibition of ERBB tyrosine kinase activity is assessed using an ELISA-based receptor tyrosine kinase assay. Kinase reactions (50 mM HEPES, pH 7.4, 125 mM NaCl, 10 mM MgCl2, 100 μM sodium orthovanadate, 2 mM dithiothreitol, 20 μM ATP, PF299804 or vehicle control, and 1-5 nM GST-erbB per 50 μL of reaction mixture) are run in 96-well plates coated with 0.25 mg/mL poly-Glu-Tyr. The reactions are incubated for 6 minutes at room temperature while being shaken. Kinase reactions are stopped by removal of the reaction mixture, and then the wells are washed with wash buffer (0.1% Tween 20 in PBS). Phosphorylated tyrosine residues are detected by adding 0.2 μg/mL antiphosphotyrosine antibody (Oncogene Ab-4; 50 μL/well) coupled to horseradish peroxidase (HRP) diluted in PBS containing 3% BSA and 0.05% Tween 20 for 25 minutes while being shaken at room temperature. The antibody is removed, and plates are washed in wash buffer. HRP substrate (SureBlue3,3,5,5-tetramethyl benzidine or TMB) is added (50 μL per well) and incubated for 10-20 minutes while it is shaken at room temperature. The TMB reaction is stopped with the addition of 50 μL of stop solution (0.09 N H2SO4). The signal is quantified by measuring absorbance at 450 nm. IC50 values are determined for PF299804 using the median effect method.

Cell Assay: [1]

Cell lines Various NSCLC cell lines
Concentrations 0-20 nM
Incubation Time 72 hours
Method Growth and inhibition of growth is assessed by 5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. This assay, a colorimetric method fordetermining the number of viable cells, is based on the bioreduction of MTS by cells to a formazan product that is soluble in cell culture medium, can be detected spectrophotometrically. The cells are exposed totreatment for 72 hours, and the number of cells used per experiment is determined empirically. All experimental points are set up in 6 to 12 wells, and all experiments are repeated at least thrice. The data are graphically displayed using GraphPad Prism version 3.00 for Windows (GraphPad Software). The curves are fitted using a nonlinear regression model with a sigmoidal dose response.

Animal Study: [1]

Animal Models HCC827-GFP or HCC827-Del/T790M lung cancer cells (in 0.2 mL of PBS) are inoculated s.c. into the lower-right quadrant of the flank of nude mice
Formulation PF299804 is dissolved in DMSO in 10 mM at -20 °
Dosages 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] Engelman JA, et al, Cancer Res, 2007, 67(24), 11924-11932.

[2] Gonzales AJ, et al, Mol Cancer Ther, 2008, 7(7), 1880-1889.

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Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-07-23)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02382796 Recruiting NSCLC Pfizer July 2015 Phase 2
NCT02268747 Active, not recruiting Skin Squamous Cell Cancer Fondazione IRCCS Istituto Nazionale dei Tumori, Milano November 2014 Phase 2
NCT02097433 Completed Healthy Pfizer July 2014 Phase 1
NCT02047747 Terminated Brain Cancer David Piccioni, M.D., Ph.D|Pfizer|University of Californi  ...more David Piccioni, M.D., Ph.D|Pfizer|University of California, San Diego February 2014 Phase 2
NCT02039336 Recruiting Colorectal Cancer The Netherlands Cancer Institute|Pfizer January 2014 Phase 1|Phase 2

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Chemical Information

Download Dacomitinib (PF299804, PF299) SDF
Molecular Weight (MW) 469.94
Formula

C24H25ClFN5O2

CAS No. 1110813-31-4
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms N/A
Solubility (25°C) * In vitro DMSO 19 mg/mL (40.43 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo 1% DMSO+30% polyethylene glycol+1% Tween 80, pH 9 10 mg/mL
* <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 (E)-N-(4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-yl)-4-(piperidin-1-yl)but-2-enamide

Customer Product Validation(3)


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Rating
Source J Immunol 2014 192(2), 722-31. Dacomitinib (PF299804, PF299) purchased from Selleck
Method ELISA
Cell Lines htSMC cells
Concentrations 50 uM
Incubation Time 24 h
Results The ErbB1/2/4 inhibitor PF299804 reduced the LPS-induced release of CXCL8.

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Rating
Source J Immunol 2014 192(2), 722-31. Dacomitinib (PF299804, PF299) purchased from Selleck
Method Flow cytometry
Cell Lines htSMC
Concentrations 50 uM
Incubation Time 24 h
Results Treatment with the EGFR kinase inhibitor PD168393, the ErbB1/2/3 inhibitor AZD8931, the ErbB1/2/4 inhibitor PF299804, or cetuximab (block of EGFR ligand binding) reduced the LPS-induced release of CXCL8 , suggesting a critical role of EGFR/ErbB1 in this response.

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Rating
Source J Immunol 2014 192(2), 722-31. Dacomitinib (PF299804, PF299) purchased from Selleck
Method Western blot
Cell Lines EPC1 cells
Concentrations 50 nM
Incubation Time 1 h
Results PF299804 was shown to inhibit bile acid-mediated EGFRphosphorylation completely.

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.

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