Clinical stage EGFR inhibitors irreversibly alkylate Bmx kinase

  • Bioorg Med Chem Lett. 2008 Nov 15;18(22):5916-9. doi: 10.1016/j.bmcl.2008.07.062.
Wooyoung Hur  1 ,  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
Affiliations
  • 1. Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA.
PMID: 18667312 DOI: 10.1016/j.bmcl.2008.07.062
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.