title: Clinical stage EGFR inhibitors irreversibly alkylate Bmx kinase.
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.
authors.affiliation: Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Wooyoung
authors.initials: W
authors.lastname: Hur
authors.forename: Anastasia
authors.initials: A
authors.lastname: Velentza
authors.forename: Sungjoon
authors.initials: S
authors.lastname: Kim
authors.forename: Laura
authors.initials: L
authors.lastname: Flatauer
authors.forename: Xinnong
authors.initials: X
authors.lastname: Jiang
authors.forename: David
authors.initials: D
authors.lastname: Valente
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Mason
authors.forename: Melissa
authors.initials: M
authors.lastname: Suzuki
authors.forename: Brad
authors.initials: B
authors.lastname: Larson
authors.forename: Jianming
authors.initials: J
authors.lastname: Zhang
authors.forename: Anna
authors.initials: A
authors.lastname: Zagorska
authors.forename: Michael
authors.initials: M
authors.lastname: Didonato
authors.forename: Advait
authors.initials: A
authors.lastname: Nagle
authors.forename: Markus
authors.initials: M
authors.lastname: Warmuth
authors.forename: Steven P
authors.initials: SP
authors.lastname: Balk
authors.forename: Eric C
authors.initials: EC
authors.lastname: Peters
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
mesh_terms: D000818:Animals; D003545:Cysteine / Q000235:genetics / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D051379:Mice; D015394:Molecular Structure; D009025:Morpholines / Q000737:chemistry / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology*; D017386:Sequence Homology, Amino Acid
chemical_list: D009025:Morpholines; C509204:PD168393; D011799:Quinazolines; C420268:Canertinib; C492366:Bmx protein, mouse; C089848:Tec protein-tyrosine kinase; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D003545:Cysteine