Dacomitinib/Dacomitinib belongs to which generation of targeted drugs

Dacomitinib/Dacomitinib is a second-generation targeted drug. The U.S. Food and Drug Administration (FDA) has approved the second-generationEGFR-targeted TKI drug dacomitinib for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) carrying EGFR Del19 or exon 21 L858R mutations. Dacotinib is a potent and irreversible pan-human epidermal growth factor receptor (HER) family inhibitor.

Dacomitinib is a multi-target irreversible inhibitor of protein kinases developed by Pfizer. Its mechanism of action is to treat cancer by inhibiting protein tyrosine kinases in cancer cells. Compared with first-generation targeted drugs, second-generation targeted drugs have higher therapeutic effects and fewer side effects. However, there are still some possible side effects, such as drug resistance and skin allergies.

In vitro and in xenograft models, dacomitinib binds an unpaired cysteine at theATP binding pocket and strongly inhibits EGFR, ErbB2 and ErbB4. Use products with L858R/T790M mutations (H1975, H3255 GR, Ba/F3) cell lines are resistant to gefitinib (IC5010μmol/L). Dacomitinib has been proven to be an effective inhibitor, with an IC50 of 0.44μmol/L and 0.11 against H1975. 9 μmol/L; Dacomitinib can also inhibit the proliferation of Ba/F3 cells expressing T790M in cis in different deletions of exon 19, with IC50s ranging from 140 to 330 nmol/L.

As an irreversible inhibitor, dacomitinib has a longer pharmacodynamic effect than first-generationTKIs. Dacomitinib also has good pharmacokinetic properties, including high oral bioavailability (>50%), high distribution volume (>17L/kg), and long half-life (>12 hours).