Clinical stage EGFR inhibitors irreversibly alkylate Bmx kinase

Irreversible HER/erbB inhibitors selectively inhibit HER-family kinases by targeting a unique cysteine residue located within the ATP-binding pocket. Sequence alignment reveals that this rare cysteine is also present in ten other protein kinases including all five Tec-family members. We demonstrate that the Tec-family kinase Bmx is potently inhibited by irreversible modification at Cys496 by clinical stage EGFR inhibitors such as CI-1033. This cross-reactivity may have significant clinical implications.

Graphical abstractQuinazoline-based clinical irriversible EGFR inhibitors is found to inhibit Tec-family kinase Bmx by covalent modification of reactive cysteine residue within active site.Figure optionsDownload full-size imageDownload as PowerPoint slide