1. JAK/STAT Signaling
    Protein Tyrosine Kinase/RTK
  2. EGFR

Dacomitinib (Synonyms: PF-00299804; PF-299804)

Cat. No.: HY-13272 Purity: 99.91%
Data Sheet SDS Handling Instructions

Dacomitinib is a specific and irreversible inhibitor of the ERBB family of kinases with IC50 of 6 nM, 45.7 nM and 73.7 nM for EGFR, ERBB2, and ERBB4, respectively.

For research use only. We do not sell to patients.
Dacomitinib Chemical Structure

Dacomitinib Chemical Structure

CAS No. : 1110813-31-4

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  • Biological Activity

  • Protocol

  • Technical Information

  • Purity & Documentation

  • References

Description

Dacomitinib is a specific and irreversible inhibitor of the ERBB family of kinases with IC50 of 6 nM, 45.7 nM and 73.7 nM for EGFR, ERBB2, and ERBB4, respectively.

IC50 & Target

IC50: 6 nM (EGFR), 45.7 nM (ERBB2), 73.7 nM (ERBB4)[1]

In Vitro

Dacomitinib (PF00299804) effectively inhibits the in vitro kinase activity of wild-type EGFR (IC50=6 nM)with similar efficacy. Dacomitinib also effectively inhibits wild-type ERBB2 with IC50 of 45.7 nM. In H441, an IC50 is reached with Dacomitinib but only at a very high concentration (4 μM) and likely reflects off-target effects. In cell lines wild-type for both EGFR and K-ras (H322, H1819, and Calu-3), Gefitinib and Dacomitinib both effectively inhibit growth of H1819 and Calu-3 cells but not of H322 cells. Dacomitinib is a pan-ERBB inhibitor and most EGFR mutant cell lines express multiple ERBB family members, the effects on EGFR phosphorylation could potentially be indirect. Dacomitinib inhibits EGFR phosphorylation in all of the different EGFR T790M proteins whereas Gefitinib is ineffective even at 10 μM. In the NIH3T3 cells, phosphorylation of EGFR L858R/T790M is completely inhibited by 1 nM Dacomitinib, whereas 100 nM or greater is required to inhibit EGFR WT/T790M or Del/T790M[1]. The HER2-amplified cell lines are most sensitive to growth inhibition by Dacomitinib (IC50<1 μM in 14 of 16 lines; 87.5%) as compared with 5 of 28 (17.9%) of HER2-nonamplified lines (excluding immortalized lines)[2].

In Vivo

To evaluate the efficacy of Dacomitinib, xenografts in nu/nu mice are generated using HCC827 GFP and HCC827 Del/T790M cells and treated the mice with Dacomitinib. Dacomitinib (10 mg/kg/d by daily oral gavage) effectively inhibits the growth of HCC827 GFP xenografts. In contrast, HCC827 Del/T790M xenografts are resistant to Gefitinib, whereas Dacomitinib treatment is substantially more effective at inhibiting growth of this xenograft model[1].

Clinical Trial
NCT Number Sponsor Condition Start Date Phase
NCT02268747 Fondazione IRCCS Istituto Nazionale dei Tumori, Milano Skin Squamous Cell Cancer November 2014 Phase 2
NCT01728233 Fondazione IRCCS Istituto Nazionale dei Tumori, Milano|Pfizer Penile Neoplasms|Carcinoma, Squamous Cell June 15, 2013 Phase 2
NCT01737008 University Health Network, Toronto Squamous Cell Carcinoma of the Head and Neck January 2013 Phase 1
NCT01796327 Pfizer Healthy Volunteers April 2013 Phase 1
NCT01918761 Central European Cooperative Oncology Group Non Small Cell Lung Cancer August 2013 Phase 1
NCT02097433 Pfizer Healthy July 2014 Phase 1
NCT02047747 David Piccioni, M.D., Ph.D|Pfizer|University of California, San Diego Brain Cancer February 2014 Phase 2
NCT01774721 SFJ Pharmaceuticals, Inc.|Pfizer EGFR Positive Non-small Cell Lung Cancer April 2013 Phase 3
NCT01571388 Pfizer Healthy|Otherwise Healthy Volunteers With Mild or Moderate Hepatic Dysfunction April 2012 Phase 1
NCT01520870 Grupo Español de Investigación en Neurooncología|Pfizer Glioblastoma|Brain Tumor, Recurrent February 2012 Phase 2
NCT01858389 Pfizer Non-small Cell Lung Cancer July 2013 Phase 2
NCT02382796 Pfizer NSCLC July 2015 Phase 2
NCT00818441 Pfizer Carcinoma, Non-small Cell March 2009 Phase 2
NCT02039336 The Netherlands Cancer Institute|Pfizer Colorectal Cancer January 2014 Phase 1|Phase 2
NCT01702506 Pfizer Healthy Volunteers October 2012 Phase 1
NCT01465802 Pfizer Non Small Cell Lung Cancer (NSCLC) December 2011 Phase 2
NCT01360554 Pfizer Non-Small Cell Lung Cancer June 16, 2011 Phase 3
NCT01920061 Pfizer Neoplasm September 10, 2013 Phase 1
NCT01449201 Yonsei University Head Neck Cancer Squamous Cell Metastatic|Head Neck Cancer Squamous Cell Recurrent October 2011 Phase 2
NCT01112527 Massachusetts General Hospital|Dana-Farber Cancer Institute|Brigham and Women's Hospital|Henry Ford Hospital|Pfizer Glioblastoma|GBM|Glioblastoma Multiforme April 2010 Phase 2
NCT01484847 University Health Network, Toronto|Pfizer Head and Neck Squamous Cell Carcinoma December 2011
NCT00971191 Pfizer Non-Small Cell Lung Cancer (NSCLC) February 2010 Phase 1
NCT00999817 Pfizer Healthy Volunteers November 2009 Phase 1
NCT00728390 Pfizer Carcinoma, Non-Small Cell|Neoplasm Metastasis July 2008 Phase 1
NCT00783328 Pfizer Neoplasms November 2008 Phase 1
NCT01116843 University Health Network, Toronto|Pfizer Oral Cavity Cancer May 2010 Phase 1|Phase 2
NCT00548093 Pfizer Carcinoma, Non Small Cell Lung April 2008 Phase 2
NCT01441128 National Cancer Institute (NCI)|National Institutes of Health Clinical Center (CC) Carcinoma, Non-Small Cell Lung|Adenocarcinoma|Carcinoma, Squamous Cell|Carcinoma, Large Cell September 1, 2011 Phase 1
NCT00768664 Pfizer Head and Neck Neoplasms November 2008 Phase 2
NCT00728468 Pfizer|Roswell Park Cancer Institute|South Texas Accelerated Research Therapeutics (START) Advanced Malignant Solid Tumors September 2008 Phase 1
NCT00225121 Pfizer Neoplasms October 2005 Phase 1
NCT00553254 Pfizer Carcinoma, Non Small Cell Lung February 2008 Phase 1|Phase 2
NCT01000025 NCIC Clinical Trials Group|Canadian Cancer Trials Group Lung Cancer September 2009 Phase 3
NCT00769067 Pfizer Non-small Cell Lung Cancer November 2008 Phase 2
NCT01121575 Pfizer Non Small Cell Lung Cancer August 2010 Phase 1
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References
Preparing Stock Solutions
Concentration Volume (DMSO) Mass 1 mg 5 mg 10 mg
1 mM 2.1279 mL 10.6397 mL 21.2793 mL
5 mM 0.4256 mL 2.1279 mL 4.2559 mL
10 mM 0.2128 mL 1.0640 mL 2.1279 mL
Kinase Assay
[1]

The catalytic domains of ERBB1, ERBB2, and ERBB4 tagged with glutathione S-transferase are expressed in insect cells and purified. ELISA-based enzyme assays and IC50 determinations for ERBB1, ERBB2, and ERBB4 are performed. Enzyme assays and IC50 determinations for all other kinases used in this study are performed[1]. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

Cell Assay
[2]

Dacomitinib (PF00299804) is prepared in DMSO and stored (−20°C), and then diluted with appropriate medium[2].

Cells are seeded in duplicate at 5×103 to 5×104 cells per well in 24-well plates, and growth inhibition data is calculated. Briefly, day after plating, Dacomitinib is added at 10 μM and 2-fold dilutions over 12 concentrations are carried out to generate a dose-response curve. Control wells without the drug are also seeded. The cells are counted on day 1 when the drug is added, as well as after 6 days when the experiment ended. After the trypsinization cells are placed in an Isotone solution and immediately counted using a Coulter Z1 particle counter. The suspension cultures are counted using a Coulter Vi-Cell counter[2]. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Administration
[1]

Dacomitinib is dissolved in DMSO and then diluted with PBS[1].

Mice[1]
Nude mice (nu/nu; 6-8 weeks old) are used for in vivo studies. Mice are anesthetized using a 2% isoflurane (Baxter) inhalation oxygen mixture. A suspension of 5×106 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 each mouse. Five mice are inoculated with either HCC827-GFP or HCC827-Del/T790M cells in the Gefitinib treatment group. Tumors are measured twice weekly using calipers, and volume is calculated using the following formula: length×width2×0.52. Mice are monitored daily for body weight and general condition. Mice are randomized to treatment when the mean tumor volume is 400 to 500 mm3. Gefitinib is administered at 150 mg/kg/d by daily oral gavage. Dacomitinib is administered at 10 mg/kg/d by daily oral gavage. The experiment is terminated when the mean size of the control tumors reached 2000 mm3. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

References
Molecular Weight

469.94

Formula

C₂₄H₂₅ClFN₅O₂

CAS No.

1110813-31-4

Storage

Please store the product under the recommended conditions in the Certificate of Analysis.

Shipping

Room temperature in continental US; may vary elsewhere

Solvent & Solubility

DMSO: ≥ 50 mg/mL (Need ultrasonic)

* "<1 mg/mL" means slightly soluble or insoluble. "≥" means soluble, but saturation unknown.

Purity: 99.91%

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Dacomitinib
Cat. No.:
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