Nazartinib is an irreversible inhibitor of mutant EGF receptors (EGFRs).1 It is selective for EGFR mutant cell lines, including H3255 and HCC827 lung adenocarcinoma cells (IC50s = 6.11 and 1.52 nM, respectively) and resistant H1975 non-small cell lung cancer cells (NSCLC; IC50 = 4.18 nM), over cells expressing wild-type EGFRs (IC50 = 160.6 nM for HaCaT keratinocytes). Nazartinib decreases phosphorylation of EGFR in H3255, HCC827, and H1975 cells (EC50s = 5, 1, and 3 nM, respectively) and inhibits cell proliferation (EC50s = 9, 11, and 25 nM, respectively) but does not affect cell proliferation in cell lines containing wild-type EGFR.2 It reduces tumor growth in an HCC827 lung adenocarcinoma mouse xenograft model when administered at doses ranging from 3 to 100 mg/kg per day for 21 days.
1.Lelais, G., Epple, R., Marsilje, T.H., et al.Discovery of (R,E)-N-(7-Chloro-1-(1-[4-(dimethylamino)but-2-enoyl]azepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide (EGF816), a novel, potent, and wt sparing covalent inhibitor of oncogenic (L858R, ex19del) and resistant (T790M) EGFR mutants for the treatment of EGFR mutant non-small-cell lung cancersJ. Med. Chem.59(14)6671-6689(2016) 2.Jia, Y., Juarez, J., Li, J., et al.EGF816 exerts anticancer effects in non-small cell lung cancer by irreversibly and selectively targeting primary and acquired activating mutations in the EGF receptorCancer Res.76(6)1591-1602(2016)