PF299804 (Dacomitinib) is an orally-available, aminoquinazoline-based, irreversible pan-HER inhibitor with IC50s of 6, 46, and 74 nM for ErbB1, ErbB2, and ErbB4, respectively. PF299804 inhibits ErbB1 autophosphorylation in A431 cells with an IC50 of 15 nM. [1]

PF299804 is known to be efficacious against EGFR-activating mutations as well as the common EGFR T790M resistance mutation which is less responsive to other therapies such as gefitinib and erlotinib. Cellular activity against EGFR and ErbB2 (NIH3T3) are 6 and 41 nM, respectively. [2]

PF299804 induces apoptosis and G1 arrest and inhibits downstream signaling pathways such as STAT3, AKT, and ERK in HER2-amplified gastric cancer cells. It is synergistic with trastuzumab as well as a host of other kinase inhibitors (IGF1R, ERK1/2, PI3K/mTOR). [3]

In a panel of almost 50 breast cancer cell lines, PF299804 induced G0 and G1 cell-cycle arrest with IC50s ranging from 5 nM to 5 uM and was active against cell lines that had acquired resistance to therapies such as trastuzumab and lapatinib. [4]