Dacomitinib (PF-00299804) is an oral, irreversible, small molecule inhibitor of human epidermal growth factor receptor-1, -2, and -4 tyrosine kinases. PF00299804 is a potent inhibitor of EGFR-activating mutations as well as the EGFR T790M resistance mutation both in vitro and in vivo. The human EGF (HER) family of receptors has been pursued as therapeutic targets in breast cancer and other malignancies. Dacomitinib inhibited growth in several HER2-amplified lines with de novo and acquired resistance to trastuzumab. Dacomitinib was administered orally at three dose levels (15, 30, or 45 mg once daily [QD]). Single-dose administration of dacomitinib plus DM was safe and well tolerated in HVs and resulted in a significant increase in systemic exposures of DM in extensive metabolizers. Additionally, PF00299804 is a highly effective inhibitor of both the wild-type ERBB2 and the gefitinib-resistant oncogenic ERBB2 mutation identified in lung cancers.
Clin Cancer Res. 2017 Oct 19;pii: clincanres.1577.2017.
Epithelial-to-mesenchymal transition antagonizes response to targeted therapies in lung cancer by suppressing BIM
Dacomitinib purchased from AbMole
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Source | Clin Cancer Res (2017). Figure 3. PF-299804 (Abmole Bioscience) |
| Method | Western blotting | |
| Cell Lines | H1975 parental cells (par), H1975 R1 cells (R1), and H1975 R2 cells (R2) | |
| Concentrations | 1 μM | |
| Incubation Time | 72 h | |
| Results | The H1975 R1 and H1975 R2 cells were developed by exposure to increasing concentrations of the pan ErbB inhibitor, second-generation EGFR inhibitor PF-299804 (dacomitinib); these cells were cross-resistant to WZ4002 (Fig. 3A) and underwent an EMT (Fig. 3B). |
| Molecular Weight | 469.94 |
| Formula | C24H25ClFN5O2 |
| CAS Number | 1110813-31-4 |
| Solubility (25°C) | DMSO ≥ 25 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
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