Dacomitinib
Dacomitinib, aslo known as PF-299 and PF-00299804 ; or PF299804, is an orally bioavailable, highly selective, second-generation small-molecule inhibitor of the pan-epidermal growth factor receptor (EGFR) family of tyrosine kinases (ErbB family) with potential antineoplastic activity. Dacomitinib specifically and irreversibly binds to and inhibits human EGFR subtypes, resulting in inhibition of proliferation and induction of apoptosis in EGFR-expressing tumor cells. EGFRs play major roles in tumor cell proliferation and tumor vascularization, and are often overexpressed or mutated in various tumor cell types.
1: Williams JP, Kim I, Ito E, Shi W, Yue S, Siu LL, Waldron J, O'Sullivan B, Yip KW, Liu FF. Pre-clinical characterization of Dacomitinib (PF-00299804), an irreversible pan-ErbB inhibitor, combined with ionizing radiation for head and neck squamous cell carcinoma. PLoS One. 2014 May 22;9(5):e98557. doi: 10.1371/journal.pone.0098557. eCollection 2014. PubMed PMID: 24853121; PubMed Central PMCID: PMC4031184.
2: Mok T, Lee K, Tang M, Leung L. Dacomitinib for the treatment of advanced or metastatic non-small-cell lung cancer. Future Oncol. 2014 Apr;10(5):813-22. doi: 10.2217/fon.14.22. PubMed PMID: 24799062.
3: Greenall SA, Donoghue JF, Gottardo NG, Johns TG, Adams TE. Glioma-specific Domain IV EGFR cysteine mutations promote ligand-induced covalent receptor dimerization and display enhanced sensitivity to dacomitinib in vivo. Oncogene. 2014 Apr 21. doi: 10.1038/onc.2014.106. [Epub ahead of print] PubMed PMID: 24747966.
4: Reckamp KL, Giaccone G, Camidge DR, Gadgeel SM, Khuri FR, Engelman JA, Koczywas M, Rajan A, Campbell AK, Gernhardt D, Ruiz-Garcia A, Letrent S, Liang J, Taylor I, O'Connell JP, Jänne PA. A phase 2 trial of dacomitinib (PF-00299804), an oral, irreversible pan-HER (human epidermal growth factor receptor) inhibitor, in patients with advanced non-small cell lung cancer after failure of prior chemotherapy and erlotinib. Cancer. 2014 Apr 15;120(8):1145-54. doi: 10.1002/cncr.28561. Epub 2014 Feb 5. PubMed PMID: 24501009; PubMed Central PMCID: PMC4164026.
5: Ruiz-Garcia A, Giri N, Labadie RR, Ni G, Boutros T, Richie N, Kocinsky HS, Checchio TM, Bello CL. A phase I open-label study to investigate the potential drug-drug interaction between single-dose dacomitinib and steady-state paroxetine in healthy volunteers. J Clin Pharmacol. 2013 Nov 30. doi: 10.1002/jcph.243. [Epub ahead of print] PubMed PMID: 24293056.
6: Grivas PD, Day KC, Karatsinides A, Paul A, Shakir N, Owainati I, Liebert M, Kunju LP, Thomas D, Hussain M, Day ML. Evaluation of the antitumor activity of dacomitinib in models of human bladder cancer. Mol Med. 2013 Nov 8;19:367-76. doi: 10.2119/molmed.2013.00108. PubMed PMID: 24166682; PubMed Central PMCID: PMC3883970.
7: Bello CL, Smith E, Ruiz-Garcia A, Ni G, Alvey C, Loi CM. A phase I, open-label, mass balance study of [(14)C] dacomitinib (PF-00299804) in healthy male volunteers. Cancer Chemother Pharmacol. 2013 Aug;72(2):379-85. doi: 10.1007/s00280-013-2207-9. Epub 2013 Jun 13. PubMed PMID: 23760812.
8: Ather F, Hamidi H, Fejzo MS, Letrent S, Finn RS, Kabbinavar F, Head C, Wong SG. Dacomitinib, an irreversible Pan-ErbB inhibitor significantly abrogates growth in head and neck cancer models that exhibit low response to cetuximab. PLoS One. 2013;8(2):e56112. doi: 10.1371/journal.pone.0056112. Epub 2013 Feb 6. PubMed PMID: 23405260; PubMed Central PMCID: PMC3566064.
9: Brzezniak C, Carter CA, Giaccone G. Dacomitinib, a new therapy for the treatment of non-small cell lung cancer. Expert Opin Pharmacother. 2013 Feb;14(2):247-53. doi: 10.1517/14656566.2013.758714. Epub 2013 Jan 7. Review. PubMed PMID: 23294134.
10: Carpenter RL, Lo HW. Dacomitinib, an emerging HER-targeted therapy for non-small cell lung cancer. J Thorac Dis. 2012 Dec;4(6):639-42. doi: 10.3978/j.issn.2072-1439.2012.10.09. PubMed PMID: 23205292; PubMed Central PMCID: PMC3506804.
2: Mok T, Lee K, Tang M, Leung L. Dacomitinib for the treatment of advanced or metastatic non-small-cell lung cancer. Future Oncol. 2014 Apr;10(5):813-22. doi: 10.2217/fon.14.22. PubMed PMID: 24799062.
3: Greenall SA, Donoghue JF, Gottardo NG, Johns TG, Adams TE. Glioma-specific Domain IV EGFR cysteine mutations promote ligand-induced covalent receptor dimerization and display enhanced sensitivity to dacomitinib in vivo. Oncogene. 2014 Apr 21. doi: 10.1038/onc.2014.106. [Epub ahead of print] PubMed PMID: 24747966.
4: Reckamp KL, Giaccone G, Camidge DR, Gadgeel SM, Khuri FR, Engelman JA, Koczywas M, Rajan A, Campbell AK, Gernhardt D, Ruiz-Garcia A, Letrent S, Liang J, Taylor I, O'Connell JP, Jänne PA. A phase 2 trial of dacomitinib (PF-00299804), an oral, irreversible pan-HER (human epidermal growth factor receptor) inhibitor, in patients with advanced non-small cell lung cancer after failure of prior chemotherapy and erlotinib. Cancer. 2014 Apr 15;120(8):1145-54. doi: 10.1002/cncr.28561. Epub 2014 Feb 5. PubMed PMID: 24501009; PubMed Central PMCID: PMC4164026.
5: Ruiz-Garcia A, Giri N, Labadie RR, Ni G, Boutros T, Richie N, Kocinsky HS, Checchio TM, Bello CL. A phase I open-label study to investigate the potential drug-drug interaction between single-dose dacomitinib and steady-state paroxetine in healthy volunteers. J Clin Pharmacol. 2013 Nov 30. doi: 10.1002/jcph.243. [Epub ahead of print] PubMed PMID: 24293056.
6: Grivas PD, Day KC, Karatsinides A, Paul A, Shakir N, Owainati I, Liebert M, Kunju LP, Thomas D, Hussain M, Day ML. Evaluation of the antitumor activity of dacomitinib in models of human bladder cancer. Mol Med. 2013 Nov 8;19:367-76. doi: 10.2119/molmed.2013.00108. PubMed PMID: 24166682; PubMed Central PMCID: PMC3883970.
7: Bello CL, Smith E, Ruiz-Garcia A, Ni G, Alvey C, Loi CM. A phase I, open-label, mass balance study of [(14)C] dacomitinib (PF-00299804) in healthy male volunteers. Cancer Chemother Pharmacol. 2013 Aug;72(2):379-85. doi: 10.1007/s00280-013-2207-9. Epub 2013 Jun 13. PubMed PMID: 23760812.
8: Ather F, Hamidi H, Fejzo MS, Letrent S, Finn RS, Kabbinavar F, Head C, Wong SG. Dacomitinib, an irreversible Pan-ErbB inhibitor significantly abrogates growth in head and neck cancer models that exhibit low response to cetuximab. PLoS One. 2013;8(2):e56112. doi: 10.1371/journal.pone.0056112. Epub 2013 Feb 6. PubMed PMID: 23405260; PubMed Central PMCID: PMC3566064.
9: Brzezniak C, Carter CA, Giaccone G. Dacomitinib, a new therapy for the treatment of non-small cell lung cancer. Expert Opin Pharmacother. 2013 Feb;14(2):247-53. doi: 10.1517/14656566.2013.758714. Epub 2013 Jan 7. Review. PubMed PMID: 23294134.
10: Carpenter RL, Lo HW. Dacomitinib, an emerging HER-targeted therapy for non-small cell lung cancer. J Thorac Dis. 2012 Dec;4(6):639-42. doi: 10.3978/j.issn.2072-1439.2012.10.09. PubMed PMID: 23205292; PubMed Central PMCID: PMC3506804.
| Chemical | |
|---|---|
| CAS Num | 1110813-31-4 |
| Chemical Formula | C24H25ClFN5O2 |
| Molecular Weight | 469.939 |
| IUPAC Chemical Name | (E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(piperidin-1-yl)but-2-enamide |
| Exact Mass | 469.16808 |
| Elemental Analysis | C, 61.34; H, 5.36; Cl, 7.54; F, 4.04; N, 14.90; O, 6.81 |
| Synonym | PF-00299804; PF00299804; PF 00299804; PF299804; PF-299804; PF 299804; PF-299; PF299; PF 299; dacomitinib |
| Solubility | Soluble in DMSO, not in water |
| SMILES Code | O=C(NC1=CC2=C(NC3=CC=C(F)C(Cl)=C3)N=CN=C2C=C1OC)/C=C/CN4CCCCC4 |
| Biological | |
| Targets and Effects | epidermal growth factor (EGF) receptor kinase INHIBITOR |
| Pathways | Apoptosis |
| Physical | |
| Appearance | White to off-white solid powder |
| Purity | >98% (or refer to the Certificate of Analysis) |
| Shipping Condition | Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs. |
| Storage Condition | Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years). |
| Shelf Life | >2 years if stored properly |
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