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.
Hur
Wooyoung
W
Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA.
Velentza
Anastasia
A
Kim
Sungjoon
S
Flatauer
Laura
L
Jiang
Xinnong
X
Valente
David
D
Mason
Daniel E
DE
Suzuki
Melissa
M
Larson
Brad
B
Zhang
Jianming
J
Zagorska
Anna
A
Didonato
Michael
M
Nagle
Advait
A
Warmuth
Markus
M
Balk
Steven P
SP
Peters
Eric C
EC
Gray
Nathanael S
NS
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
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