Biomedical properties of dacomitinib (PF299804)

Figure 1. Structural formula of dacomitinib (PF299804)

Dacomitinib (PF299804), which name is (E)-N-[4-(3-chloro-4-fluoroanilino)-7- methoxyquinazolin-6-yl]-4-piperidin-1-ylbut-2-enamide, is a potent, orally available, highly selective, irreversible small-molecule tyrosine kinase inhibitor (TKI) of tyrosine kinase human epidermal growth factor receptors (HER) 1 (EGFR), HER2, and HER4. It is most effective against EGFR with IC50 of 6 nM. It is highly effective against NSCLCs carrying EGFR or ERBB2 mutant (anti-Gefitinib) and EGFR T790M mutant. Irreversible receptor inhibition has the potential to improve antitumor activity and overcome mechanisms of resistance to reversible EGFR TKIs gefitinib and erlotinib. Preclinical studies demonstrate that PF299804 is effective against gefitinib resistant (EGFR exon 20 insertion and T790M) mutations. This first-in-human study of PF299804 in patients with advanced solid malignancies showed that it has a manageable safety profile, is well tolerated on continuous and intermittent schedules, with dose-proportional pharmacokinetics, and demonstrated a dose-dependent increase in target inhibition. This study included 57 NSCLC patients, the majority of whom previously received gefitinib or erlotinib. 

PF299804 offers potential advances in targeting the HER signaling pathways. PF299804 achieves irreversible inhibition via covalent modification of nucleophilic cysteine residues in the catalytic domains of the HER family receptors. Irreversible inhibitors induce prolonged suppression of tyrosine kinase activity compared with reversible inhibitors, leading to improved antitumor activity in preclinical models. The T790M mutation leads to an increase in the affinity of EGFR for ATP, thus dramatically reducing the efficacy of reversible quinazoline inhibitors like gefitinib and erlotinib. Irreversible inhibitors achieve greater occupancy at the ATP site leading to inhibition of EGFR T790M despite the increased affinity of the receptor for ATP. PF299804 inhibits not only wild-type and the common activating mutations of the EGFR, but also demonstrates significant preclinical activity against tumors bearing the T790M mutation both in vitro and in vivo. PF299804 is also highly effective in lung cancer models with activating EGFR mutations that are resistant to gefitinib alone such as the EGFR exon 20 insertion mutations. In contrast to gefitinib or erlotinib, PF299804 inhibits all 3 kinase-active members of the HER family. This may be advantageous in treating cancers, such as NSCLC, where genomic alterations involving multiple HER family have been described. In fact preclinical studies have demonstrated that PF299804 is also effective against NSCLC models harboring either HER2 amplifications or mutations. 

Preclinically, PF299804 shows promising pharmacokinetic properties across species and has a higher bioavailability, longer half-life, and larger volume of distribution than CI-1033, a first-generation, irreversible, pan-HER inhibitor. 

Dacomitinib (PF299804) is a scientific research reagent, which is widely used in molecular biology, pharmacology and other related scientific research experiments, such as kinase experiments, cell experiments and animal experiments, etc., however, it is strictly prohibited for human use.  

References

[1] Pasi A. Jänne, David S. Boss, D. Ross Camidge, et al. Phase I Dose-Escalation Study of the Pan-HER Inhibitor, PF299804, in Patients with Advanced Malignant Solid Tumors[J]. Clinical Cancer Research. 2011, 17,5. 
[2] 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 Dec 15;67(24):11924-32.
[3] 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 Sep;11(9):1978-87.
[4] https://pubs.acs.org/doi/10.1021/bk-2016-1239.ch008
[5] http://www.chemspider.com/Chemical-Structure.9685914.html?rid=7e3edb78-25be-424d-9f26-6674d31a5513&page_num=0

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