Bioorganic & Medicinal Chemistry Letters 2008-11-15

Clinical stage EGFR inhibitors irreversibly alkylate Bmx kinase.

Wooyoung Hur, Anastasia Velentza, Sungjoon Kim, Laura Flatauer, Xinnong Jiang, David Valente, Daniel E Mason, Melissa Suzuki, Brad Larson, Jianming Zhang, Anna Zagorska, Michael Didonato, Advait Nagle, Markus Warmuth, Steven P Balk, Eric C Peters, Nathanael S Gray

Index: Bioorg. Med. Chem. Lett. 18(22) , 5916-9, (2008)

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Abstract

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.