A small molecule-kinase interaction map for clinical kinase inhibitors.
Kinase inhibitors show great promise as a new class of therapeutics. Here we describe an efficient way to determine kinase inhibitor specificity by measuring binding of small molecules to the ATP site of kinases. We have profiled 20 kinase inhibitors, including 16 that are approved drugs or in clinical development, against a panel of 119 protein kinases. We find that specificity varies widely and is not strongly correlated with chemical structure or the identity of the intended target. Many novel interactions were identified, including tight binding of the p38 inhibitor BIRB-796 to an imatinib-resistant variant of the ABL kinase, and binding of imatinib to the SRC-family kinase LCK. We also show that mutations in the epidermal growth factor receptor (EGFR) found in gefitinib-responsive patients do not affect the binding affinity of gefitinib or erlotinib. Our results represent a systematic small molecule-protein interaction map for clinical compounds across a large number of related proteins.
Fabian
Miles A
MA
Ambit Biosciences, 4215 Sorrento Valley Blvd., San Diego, California 92121, USA.
Biggs
William H
WH
Treiber
Daniel K
DK
Atteridge
Corey E
CE
Azimioara
Mihai D
MD
Benedetti
Michael G
MG
Carter
Todd A
TA
Ciceri
Pietro
P
Edeen
Philip T
PT
Floyd
Mark
M
Ford
Julia M
JM
Galvin
Margaret
M
Gerlach
Jay L
JL
Grotzfeld
Robert M
RM
Herrgard
Sanna
S
Insko
Darren E
DE
Insko
Michael A
MA
Lai
Andiliy G
AG
Lélias
Jean-Michel
JM
Mehta
Shamal A
SA
Milanov
Zdravko V
ZV
Velasco
Anne Marie
AM
Wodicka
Lisa M
LM
Patel
Hitesh K
HK
Zarrinkar
Patrick P
PP
Lockhart
David J
DJ
D001549:Benzamides; D015195:Drug Design; D004926:Escherichia coli / Q000378:metabolism*; D029968:Escherichia coli Proteins / Q000378:metabolism*; D000068877:Imatinib Mesylate; D008832:Microchemistry / Q000379:methods; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010879:Piperazines / Q000378:metabolism*; D011485:Protein Binding; D025941:Protein Interaction Mapping / Q000379:methods*; D047428:Protein Kinase Inhibitors / Q000378:metabolism*; D011743:Pyrimidines / Q000378:metabolism*
D001549:Benzamides; D029968:Escherichia coli Proteins; D004364:Pharmaceutical Preparations; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate