WZ4002

WZ4002 is an irreversible EGFR tyrosine kinase inhibitor that blocks ATP-dependent autophosphorylation of EGFR carrying the T790M mutation as well as an L858R mutation (IC₅₀ = 8 nM).^1,2 It preferentially targets cells expressing EGFR^T790M over those expressing EGFR without the T790M mutation.¹ WZ4002 is also bioavailable in vivo when given intravenously and is effective in mouse models of lung cancer driven by EGFR^T790M.¹ Efficacy may be enhanced when used in combination therapy with inhibitors of Met kinase activity, Bcl-2, or histone deacetylases.^3,4,5,6

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1. Zhou, W., Ercan, D., Chen, L., et al. Novel mutant-selective EGFR kinase inhibitors against EGFR T790M. Nature 462(7276), 1070-1074 (2009).

2. Lee, H.J., Schaefer, G., Heffron, T.P., et al. Noncovalent wild-type-sparing inhibitors of EGFR T790M. Cancer Discov. 3(2), 168-181 (2013).

3. Wang, W., Li, Q., Takeuchi, S., et al. Met kinase inhibitor E7050 reverses three different mechanisms of hepatocyte growth factor-induced tyrosine kinase inhibitor resistance in EGFR mutant lung cancer. Clin. Cancer Res. 18(6), 1663-1671 (2012).

4. Nakagawa, T., Takeuchi, S., Yamada, T., et al. Combined therapy with mutant-selective EGFR inhibitor and Met kinase inhibitor for overcoming erlotinib resistance in EGFR-mutant lung cancer. Mol. Cancer Ther. 11(10), 2149-2157 (2012).

5. Sakuma, Y., Yamazaki, Y., Nakamura, Y., et al. WZ4002, a third-generation EGFR inhibitor, can overcome anoikis resistance in EGFR-mutant lung adenocarcinomas more efficiently than Src inhibitors. Lab. Invest. 92(3), 371-383 (2012).

6. Nanjo, S., Yamada, T., Nishihara, H., et al. Ability of the Met kinase inhibitor crizotinib and new generation EGFR inhibitors to overcome resistance to EGFR inhibitors. PLoS One 8(12), 1-13 (2013).