WZ8040 is a novel mutant-selective irreversible EGFRT790M inhibitor, does not inhibit ERBB2 phosphorylation (T798I).
WZ8040 is 30- to 100-fold more potent against EGFR T790M, and up to 100-fold less potent against wild-type EGFR, than quinazoline-based EGFR inhibitors such as CL-387785 and HKI-272. WZ8040 treatment potently inhibits the growth of HCC827 (EGFR Del E746_A750), PC9 (EGFR Del E746_A750), H3255 (EGFR L858R), H1975 (EGFR L858R/T790M), and PC9 GR (EGFR Del E746_A750/T790M) with IC50 of 1 nM, 6 nM, 66 nM, 9 nM, and 8 nM, respectively. WZ8040 weakly inhibits the growth of HCC827 GR (EGFR E746_A750/MET amp), H1819 (ERBB2 amp), Calu-3 (ERBB2 amp), H1781 (ERBB2 Ins G776V, C), and HN11 (EGFR & ERBB2 WT) with IC50 of >3.3 μM, 738 nM, 915 nM, 744 nM, and 1.82 μM, respectively. WZ8040 is not toxic up to 10 μM against A549 (KRAS mutant) or H3122 (EML4-ALK) cells.
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