Cat. No. Name Size Price Add Cart
KI1063PF2998045 mg$272
PF29980410 mg$512
PF29980450 mg$1552
PF299804200 mg$3952

Chemical Characteristic

Product NamePF299804
SynonymsDacomitinib, PF-00299804
CAS No.1110813-31-4
Molecular Weight 469.94
FormulaC24H25ClFN5O2
Chemical Name(2E)-N-[4-[(3-Chloro-4-fluorophenyl)amino]-7-methoxy-6-quinazolinyl]-4-(1-piperidinyl)-2-butenamide
SmilesC(=O)(/C=C/CN1CCCCC1)Nc1cc2c(ncnc2cc1OC)Nc1cc(c(cc1)F)Cl
Chemical Structure

Biological activities

PF299804 is an irreversible Pan-ERBB inhibitor. The IC50 of PF299804 is 6, 45.7 and 73.7 nM against EGFR, ERBB2 and ERBB4, respectively. PF299804 inhibits NIH-3T3 cells expressing EGFR with an IC50 of 5.8 nM. In contrast, PF299804 inhibits NIH3T3 cells expressing ERBB2 with 41 nM. PF299804 effectively inhibits growth of H1819 and Calu-3 cells but not of H322 cells. In H3255 GR, PF299804 completely inhibits EGFR, ERBB3, and Akt phosphorylation. PF299804 prevents the growth of H3255 and HCC827 cells engineered to express EGFRT790M.[1] PF299804 irreversibly inhibits 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 induces apoptosis and G(1) arrest and inhibited 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 prevents EGFR/HER2, HER2/HER3, and HER3/HER4 heterodimer formation as well as the association of HER3 with p85α in SNU216 cells.[3] PF299804 exerts its antiproliferative effect through a combined G(0)-G(1) arrest and an induction of apoptosis. PF299804 prevents growth in several HER2-amplified lines with de novo and acquired resistance to trastuzumab.[4] Oral administration of PF299804 gives rise to 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]

Protocols

In vitro PF299804 is prepared in DMSO and stored at -20°C.[1]

References

[1] Engelman JA, et al. PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib. Cancer Res. 2007, 67(24): 11924-11932.
[2] Gonzales AJ, et al. Antitumor activity and pharmacokinetic properties of PF-00299804, a second-generation irreversible pan-erbB receptor tyrosine kinase inhibitor. Mol Cancer Ther. 2008, 7(7): 1880-1889.
[3] Nam HJ, et al. Evaluation of the antitumor effects and mechanisms of PF00299804, a pan-HER inhibitor, alone or in combination with chemotherapy or targeted agents in gastric cancer.Mol Cancer Ther. 2012, 11(2): 439-451.
[4] Kalous O, et al. Dacomitinib (PF-00299804), an irreversible Pan-HER inhibitor, inhibits proliferation of HER2-amplified breast cancer cell lines resistant to trastuzumab and lapatinib. Mol Cancer Ther. 2012, 11(9): 1978-1987.

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