Comprehensive analysis of kinase inhibitor selectivity.

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Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP

Comprehensive analysis of kinase inhibitor selectivity.

Nat Biotechnol. 2011 Oct 30;29(11):1046-51. doi: 10.1038/nbt.1990.

PubMed ID
22037378 [ View in PubMed
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Abstract

We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
A-674563cAMP-dependent protein kinase catalytic subunit alphaKd (nM)56N/AN/ADetails
AfatinibEpidermal growth factor receptorKd (nM)0.25N/AN/ADetails
AfatinibEpidermal growth factor receptorKd (nM)0.11N/AN/ADetails
AfatinibEpidermal growth factor receptorKd (nM)0.1N/AN/ADetails
AfatinibEpidermal growth factor receptorKd (nM)0.19N/AN/ADetails
AfatinibEpidermal growth factor receptorKd (nM)0.14N/AN/ADetails
AfatinibEpidermal growth factor receptorKd (nM)0.12N/AN/ADetails
AfatinibEpidermal growth factor receptorKd (nM)0.2N/AN/ADetails
AfatinibEpidermal growth factor receptorKd (nM)1.1N/AN/ADetails
AfatinibEpidermal growth factor receptorKd (nM)0.23N/AN/ADetails
AfatinibEpidermal growth factor receptorKd (nM)0.61N/AN/ADetails
AfatinibReceptor tyrosine-protein kinase erbB-2Kd (nM)5N/AN/ADetails
AfatinibReceptor tyrosine-protein kinase erbB-4Kd (nM)6.3N/AN/ADetails
AlvocidibCyclin-dependent kinase 2Kd (nM)550N/AN/ADetails
AlvocidibCyclin-dependent kinase 4Kd (nM)9N/AN/ADetails
AlvocidibCyclin-dependent kinase 4Kd (nM)3.3N/AN/ADetails
AlvocidibCyclin-dependent kinase 5Kd (nM)110N/AN/ADetails
AlvocidibCyclin-dependent kinase 7Kd (nM)23N/AN/ADetails
AlvocidibCyclin-dependent kinase 8Kd (nM)120N/AN/ADetails
AlvocidibCyclin-dependent kinase 9Kd (nM)6.4N/AN/ADetails
AlvocidibEpidermal growth factor receptorKd (nM)2300N/AN/ADetails
AlvocidibEpidermal growth factor receptorKd (nM)1400N/AN/ADetails
AlvocidibEpidermal growth factor receptorKd (nM)3700N/AN/ADetails
AlvocidibEpidermal growth factor receptorKd (nM)1200N/AN/ADetails
AlvocidibEpidermal growth factor receptorKd (nM)520N/AN/ADetails
AlvocidibEpidermal growth factor receptorKd (nM)4000N/AN/ADetails
AlvocidibEpidermal growth factor receptorKd (nM)2200N/AN/ADetails
AlvocidibEpidermal growth factor receptorKd (nM)3000N/AN/ADetails
AlvocidibEpidermal growth factor receptorKd (nM)1700N/AN/ADetails
AlvocidibEpidermal growth factor receptorKd (nM)750N/AN/ADetails
AlvocidibEpidermal growth factor receptorKd (nM)1600N/AN/ADetails
AT-7519Cyclin-dependent kinase 2Kd (nM)30N/AN/ADetails
BosutinibCalcium/calmodulin-dependent protein kinase type II subunit gammaKd (nM)3600N/AN/ADetails
BosutinibCyclin-dependent kinase 2Kd (nM)>10000N/AN/ADetails
BosutinibDual specificity mitogen-activated protein kinase kinase 1Kd (nM)19N/AN/ADetails
BosutinibDual specificity mitogen-activated protein kinase kinase 2Kd (nM)9.9N/AN/ADetails
BosutinibMitogen-activated protein kinase kinase kinase 2Kd (nM)30N/AN/ADetails
BosutinibProto-oncogene tyrosine-protein kinase SrcKd (nM)1N/AN/ADetails
BosutinibTyrosine-protein kinase ABL1Kd (nM)0.047N/AN/ADetails
BosutinibTyrosine-protein kinase ABL1Kd (nM)0.63N/AN/ADetails
BosutinibTyrosine-protein kinase ABL1Kd (nM)0.18N/AN/ADetails
BosutinibTyrosine-protein kinase ABL1Kd (nM)0.11N/AN/ADetails
BosutinibTyrosine-protein kinase ABL1Kd (nM)0.029N/AN/ADetails
BosutinibTyrosine-protein kinase ABL1Kd (nM)0.062N/AN/ADetails
BosutinibTyrosine-protein kinase ABL1Kd (nM)0.057N/AN/ADetails
BosutinibTyrosine-protein kinase ABL1Kd (nM)0.037N/AN/ADetails
BosutinibTyrosine-protein kinase ABL1Kd (nM)0.086N/AN/ADetails
BosutinibTyrosine-protein kinase ABL1Kd (nM)0.039N/AN/ADetails
BosutinibTyrosine-protein kinase ABL1Kd (nM)21N/AN/ADetails
BosutinibTyrosine-protein kinase ABL1Kd (nM)3.6N/AN/ADetails
BosutinibTyrosine-protein kinase ABL1Kd (nM)0.036N/AN/ADetails
BosutinibTyrosine-protein kinase ABL1Kd (nM)0.12N/AN/ADetails
BosutinibTyrosine-protein kinase HCKKd (nM)3.4N/AN/ADetails
BosutinibTyrosine-protein kinase LynKd (nM)4.2N/AN/ADetails
CanertinibEpidermal growth factor receptorKd (nM)0.19N/AN/ADetails
CanertinibEpidermal growth factor receptorKd (nM)0.17N/AN/ADetails
CanertinibEpidermal growth factor receptorKd (nM)0.26N/AN/ADetails
CanertinibEpidermal growth factor receptorKd (nM)0.22N/AN/ADetails
CanertinibEpidermal growth factor receptorKd (nM)0.13N/AN/ADetails
CanertinibEpidermal growth factor receptorKd (nM)0.24N/AN/ADetails
CanertinibEpidermal growth factor receptorKd (nM)0.28N/AN/ADetails
CanertinibEpidermal growth factor receptorKd (nM)0.1N/AN/ADetails
CediranibVascular endothelial growth factor receptor 2Kd (nM)1.1N/AN/ADetails
CrizotinibALK tyrosine kinase receptorKd (nM)3.3N/AN/ADetails
CrizotinibHepatocyte growth factor receptorKd (nM)2.1N/AN/ADetails
CrizotinibHepatocyte growth factor receptorKd (nM)0.55N/AN/ADetails
CrizotinibHepatocyte growth factor receptorKd (nM)1.5N/AN/ADetails
DasatinibAbelson tyrosine-protein kinase 2Kd (nM)0.17N/AN/ADetails
DasatinibEphrin type-A receptor 2Kd (nM)0.85N/AN/ADetails
DasatinibEphrin type-B receptor 4Kd (nM)0.34N/AN/ADetails
DasatinibMitogen-activated protein kinase 14Kd (nM)27N/AN/ADetails
DasatinibPlatelet-derived growth factor receptor betaKd (nM)0.63N/AN/ADetails
DasatinibProto-oncogene tyrosine-protein kinase SrcKd (nM)0.21N/AN/ADetails
DasatinibTyrosine-protein kinase ABL1Kd (nM)0.047N/AN/ADetails
DasatinibTyrosine-protein kinase ABL1Kd (nM)0.1N/AN/ADetails
DasatinibTyrosine-protein kinase ABL1Kd (nM)0.041N/AN/ADetails
DasatinibTyrosine-protein kinase ABL1Kd (nM)0.032N/AN/ADetails
DasatinibTyrosine-protein kinase ABL1Kd (nM)0.019N/AN/ADetails
DasatinibTyrosine-protein kinase ABL1Kd (nM)0.025N/AN/ADetails
DasatinibTyrosine-protein kinase ABL1Kd (nM)0.046N/AN/ADetails
DasatinibTyrosine-protein kinase ABL1Kd (nM)0.016N/AN/ADetails
DasatinibTyrosine-protein kinase ABL1Kd (nM)0.037N/AN/ADetails
DasatinibTyrosine-protein kinase ABL1Kd (nM)0.064N/AN/ADetails
DasatinibTyrosine-protein kinase ABL1Kd (nM)890N/AN/ADetails
DasatinibTyrosine-protein kinase ABL1Kd (nM)120N/AN/ADetails
DasatinibTyrosine-protein kinase ABL1Kd (nM)0.058N/AN/ADetails
DasatinibTyrosine-protein kinase ABL1Kd (nM)0.029N/AN/ADetails
DasatinibTyrosine-protein kinase BTKKd (nM)1.4N/AN/ADetails
DasatinibTyrosine-protein kinase CSKKd (nM)1N/AN/ADetails
DasatinibTyrosine-protein kinase FRKKd (nM)0.31N/AN/ADetails
DasatinibTyrosine-protein kinase FynKd (nM)0.79N/AN/ADetails
DasatinibTyrosine-protein kinase LckKd (nM)0.2N/AN/ADetails
DasatinibTyrosine-protein kinase LynKd (nM)0.57N/AN/ADetails
DasatinibTyrosine-protein kinase YesKd (nM)0.3N/AN/ADetails
DoramapimodMitogen-activated protein kinase 14Kd (nM)0.45N/AN/ADetails
ErlotinibEpidermal growth factor receptorKd (nM)0.67N/AN/ADetails
ErlotinibEpidermal growth factor receptorKd (nM)0.52N/AN/ADetails
ErlotinibEpidermal growth factor receptorKd (nM)0.47N/AN/ADetails
ErlotinibEpidermal growth factor receptorKd (nM)1.2N/AN/ADetails
ErlotinibEpidermal growth factor receptorKd (nM)1.6N/AN/ADetails
ErlotinibEpidermal growth factor receptorKd (nM)0.48N/AN/ADetails
ErlotinibEpidermal growth factor receptorKd (nM)0.85N/AN/ADetails
ErlotinibEpidermal growth factor receptorKd (nM)0.35N/AN/ADetails
ErlotinibEpidermal growth factor receptorKd (nM)0.97N/AN/ADetails
ErlotinibEpidermal growth factor receptorKd (nM)190N/AN/ADetails
ErlotinibEpidermal growth factor receptorKd (nM)140N/AN/ADetails
ImatinibEpithelial discoidin domain-containing receptor 1Kd (nM)0.7N/AN/ADetails
ImatinibHigh affinity nerve growth factor receptorKd (nM)>10000N/AN/ADetails
ImatinibMacrophage colony-stimulating factor 1 receptorKd (nM)11N/AN/ADetails
ImatinibPlatelet-derived growth factor receptor alphaKd (nM)31N/AN/ADetails
ImatinibPlatelet-derived growth factor receptor betaKd (nM)14N/AN/ADetails
ImatinibTyrosine-protein kinase ABL1Kd (nM)44N/AN/ADetails
ImatinibTyrosine-protein kinase ABL1Kd (nM)110N/AN/ADetails
ImatinibTyrosine-protein kinase ABL1Kd (nM)21N/AN/ADetails
ImatinibTyrosine-protein kinase ABL1Kd (nM)>10000N/AN/ADetails
ImatinibTyrosine-protein kinase ABL1Kd (nM)170N/AN/ADetails
ImatinibTyrosine-protein kinase ABL1Kd (nM)8.3N/AN/ADetails
ImatinibTyrosine-protein kinase ABL1Kd (nM)580N/AN/ADetails
ImatinibTyrosine-protein kinase ABL1Kd (nM)2.5N/AN/ADetails
ImatinibTyrosine-protein kinase ABL1Kd (nM)5.9N/AN/ADetails
ImatinibTyrosine-protein kinase ABL1Kd (nM)92N/AN/ADetails
ImatinibTyrosine-protein kinase ABL1Kd (nM)1.8N/AN/ADetails
ImatinibTyrosine-protein kinase ABL1Kd (nM)65N/AN/ADetails
ImatinibTyrosine-protein kinase ABL1Kd (nM)130N/AN/ADetails
ImatinibTyrosine-protein kinase ABL1Kd (nM)1.1N/AN/ADetails
LapatinibEpidermal growth factor receptorKd (nM)2.4N/AN/ADetails
LapatinibEpidermal growth factor receptorKd (nM)2.1N/AN/ADetails
LapatinibEpidermal growth factor receptorKd (nM)2.2N/AN/ADetails
LapatinibEpidermal growth factor receptorKd (nM)3.9N/AN/ADetails
LapatinibEpidermal growth factor receptorKd (nM)1.2N/AN/ADetails
LapatinibEpidermal growth factor receptorKd (nM)2.8N/AN/ADetails
LapatinibEpidermal growth factor receptorKd (nM)0.92N/AN/ADetails
LapatinibEpidermal growth factor receptorKd (nM)4.2N/AN/ADetails
LapatinibEpidermal growth factor receptorKd (nM)8.6N/AN/ADetails
LapatinibEpidermal growth factor receptorKd (nM)3.5N/AN/ADetails
LapatinibEpidermal growth factor receptorKd (nM)>10000N/AN/ADetails
LapatinibEpidermal growth factor receptorKd (nM)860N/AN/ADetails
LapatinibReceptor tyrosine-protein kinase erbB-2Kd (nM)7N/AN/ADetails
NeflamapimodMitogen-activated protein kinase 14Kd (nM)2.8N/AN/ADetails
NilotinibTyrosine-protein kinase ABL1Kd (nM)4.9N/AN/ADetails
NilotinibTyrosine-protein kinase ABL1Kd (nM)21N/AN/ADetails
NilotinibTyrosine-protein kinase ABL1Kd (nM)15N/AN/ADetails
NilotinibTyrosine-protein kinase ABL1Kd (nM)10N/AN/ADetails
NilotinibTyrosine-protein kinase ABL1Kd (nM)660N/AN/ADetails
NilotinibTyrosine-protein kinase ABL1Kd (nM)>10000N/AN/ADetails
NilotinibTyrosine-protein kinase ABL1Kd (nM)13N/AN/ADetails
NilotinibTyrosine-protein kinase ABL1Kd (nM)36N/AN/ADetails
NilotinibTyrosine-protein kinase ABL1Kd (nM)18N/AN/ADetails
NilotinibTyrosine-protein kinase ABL1Kd (nM)56N/AN/ADetails
NilotinibTyrosine-protein kinase ABL1Kd (nM)12N/AN/ADetails
NilotinibTyrosine-protein kinase ABL1Kd (nM)14N/AN/ADetails
PazopanibPlatelet-derived growth factor receptor alphaKd (nM)4.9N/AN/ADetails
PazopanibPlatelet-derived growth factor receptor betaKd (nM)2N/AN/ADetails
PazopanibTyrosine-protein kinase ITK/TSKKd (nM)>10000N/AN/ADetails
PazopanibVascular endothelial growth factor receptor 1Kd (nM)14N/AN/ADetails
PazopanibVascular endothelial growth factor receptor 2Kd (nM)14N/AN/ADetails
PazopanibVascular endothelial growth factor receptor 3Kd (nM)27N/AN/ADetails
PLX-4720Serine/threonine-protein kinase B-rafKd (nM)330N/AN/ADetails
PLX-4720Serine/threonine-protein kinase B-rafKd (nM)100N/AN/ADetails
RO-4584820Cyclin-dependent kinase 2Kd (nM)0.53N/AN/ADetails
RuxolitinibTyrosine-protein kinase JAK2Kd (nM)0.036N/AN/ADetails
SorafenibFibroblast growth factor receptor 1Kd (nM)2800N/AN/ADetails
SorafenibPlatelet-derived growth factor receptor betaKd (nM)37N/AN/ADetails
SorafenibProto-oncogene tyrosine-protein kinase receptor RetKd (nM)13N/AN/ADetails
SorafenibProto-oncogene tyrosine-protein kinase receptor RetKd (nM)7.4N/AN/ADetails
SorafenibProto-oncogene tyrosine-protein kinase receptor RetKd (nM)39N/AN/ADetails
SorafenibProto-oncogene tyrosine-protein kinase receptor RetKd (nM)22N/AN/ADetails
SorafenibRAF proto-oncogene serine/threonine-protein kinaseKd (nM)230N/AN/ADetails
SorafenibReceptor-type tyrosine-protein kinase FLT3Kd (nM)13N/AN/ADetails
SorafenibReceptor-type tyrosine-protein kinase FLT3Kd (nM)82N/AN/ADetails
SorafenibReceptor-type tyrosine-protein kinase FLT3Kd (nM)30N/AN/ADetails
SorafenibReceptor-type tyrosine-protein kinase FLT3Kd (nM)79N/AN/ADetails
SorafenibReceptor-type tyrosine-protein kinase FLT3Kd (nM)11N/AN/ADetails
SorafenibReceptor-type tyrosine-protein kinase FLT3Kd (nM)17N/AN/ADetails
SorafenibReceptor-type tyrosine-protein kinase FLT3Kd (nM)4.5N/AN/ADetails
SorafenibSerine/threonine-protein kinase B-rafKd (nM)540N/AN/ADetails
SorafenibSerine/threonine-protein kinase B-rafKd (nM)260N/AN/ADetails
SorafenibVascular endothelial growth factor receptor 1Kd (nM)31N/AN/ADetails
SorafenibVascular endothelial growth factor receptor 2Kd (nM)59N/AN/ADetails
SorafenibVascular endothelial growth factor receptor 3Kd (nM)95N/AN/ADetails
Staurosporine3-phosphoinositide-dependent protein kinase 1Kd (nM)1.7N/AN/ADetails
StaurosporineCyclin-dependent kinase 2Kd (nM)7N/AN/ADetails
StaurosporineGlycogen synthase kinase-3 betaKd (nM)69N/AN/ADetails
StaurosporineMAP kinase-activated protein kinase 2Kd (nM)880N/AN/ADetails
StaurosporinePhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoformKd (nM)1800N/AN/ADetails
StaurosporineProtein kinase C theta typeKd (nM)8.5N/AN/ADetails
StaurosporineSerine/threonine-protein kinase pim-1Kd (nM)3.2N/AN/ADetails
StaurosporineTyrosine-protein kinase CSKKd (nM)330N/AN/ADetails
StaurosporineTyrosine-protein kinase ITK/TSKKd (nM)19N/AN/ADetails
StaurosporineTyrosine-protein kinase LckKd (nM)30N/AN/ADetails
StaurosporineTyrosine-protein kinase SYKKd (nM)14N/AN/ADetails
StaurosporineTyrosine-protein kinase ZAP-70Kd (nM)44N/AN/ADetails
SunitinibMacrophage colony-stimulating factor 1 receptorKd (nM)2.5N/AN/ADetails
SunitinibPlatelet-derived growth factor receptor alphaKd (nM)0.79N/AN/ADetails
SunitinibPlatelet-derived growth factor receptor betaKd (nM)0.075N/AN/ADetails
SunitinibReceptor-type tyrosine-protein kinase FLT3Kd (nM)2.3N/AN/ADetails
SunitinibReceptor-type tyrosine-protein kinase FLT3Kd (nM)4.3N/AN/ADetails
SunitinibReceptor-type tyrosine-protein kinase FLT3Kd (nM)0.99N/AN/ADetails
SunitinibReceptor-type tyrosine-protein kinase FLT3Kd (nM)2.4N/AN/ADetails
SunitinibReceptor-type tyrosine-protein kinase FLT3Kd (nM)0.41N/AN/ADetails
SunitinibReceptor-type tyrosine-protein kinase FLT3Kd (nM)0.22N/AN/ADetails
SunitinibReceptor-type tyrosine-protein kinase FLT3Kd (nM)11N/AN/ADetails
SunitinibVascular endothelial growth factor receptor 1Kd (nM)1.8N/AN/ADetails
SunitinibVascular endothelial growth factor receptor 2Kd (nM)1.5N/AN/ADetails
SunitinibVascular endothelial growth factor receptor 3Kd (nM)50N/AN/ADetails
TamatinibTyrosine-protein kinase SYKKd (nM)19N/AN/ADetails
TandutinibReceptor-type tyrosine-protein kinase FLT3Kd (nM)3N/AN/ADetails
TandutinibReceptor-type tyrosine-protein kinase FLT3Kd (nM)310N/AN/ADetails
TandutinibReceptor-type tyrosine-protein kinase FLT3Kd (nM)1800N/AN/ADetails
TandutinibReceptor-type tyrosine-protein kinase FLT3Kd (nM)9.1N/AN/ADetails
TandutinibReceptor-type tyrosine-protein kinase FLT3Kd (nM)29N/AN/ADetails
TandutinibReceptor-type tyrosine-protein kinase FLT3Kd (nM)1.5N/AN/ADetails
TandutinibReceptor-type tyrosine-protein kinase FLT3Kd (nM)410N/AN/ADetails
TofacitinibNon-receptor tyrosine-protein kinase TYK2Kd (nM)4.8N/AN/ADetails
TofacitinibNon-receptor tyrosine-protein kinase TYK2Kd (nM)>10000N/AN/ADetails
TofacitinibTyrosine-protein kinase JAK2Kd (nM)0.58N/AN/ADetails
TofacitinibTyrosine-protein kinase JAK3Kd (nM)0.16N/AN/ADetails
VandetanibAngiopoietin-1 receptorKd (nM)1000N/AN/ADetails
VandetanibEpidermal growth factor receptorKd (nM)5.9N/AN/ADetails
VandetanibEpidermal growth factor receptorKd (nM)12N/AN/ADetails
VandetanibEpidermal growth factor receptorKd (nM)7.9N/AN/ADetails
VandetanibEpidermal growth factor receptorKd (nM)8.7N/AN/ADetails
VandetanibEpidermal growth factor receptorKd (nM)11N/AN/ADetails
VandetanibEpidermal growth factor receptorKd (nM)9.6N/AN/ADetails
VandetanibEpidermal growth factor receptorKd (nM)9.5N/AN/ADetails
VandetanibEpidermal growth factor receptorKd (nM)4.8N/AN/ADetails
VandetanibEpidermal growth factor receptorKd (nM)8.9N/AN/ADetails
VandetanibEpidermal growth factor receptorKd (nM)230N/AN/ADetails
VandetanibEpidermal growth factor receptorKd (nM)100N/AN/ADetails
VandetanibProtein-tyrosine kinase 6Kd (nM)160N/AN/ADetails
VandetanibProto-oncogene tyrosine-protein kinase receptor RetKd (nM)34N/AN/ADetails
VandetanibProto-oncogene tyrosine-protein kinase receptor RetKd (nM)14N/AN/ADetails
VandetanibProto-oncogene tyrosine-protein kinase receptor RetKd (nM)>10000N/AN/ADetails
VatalanibVascular endothelial growth factor receptor 1Kd (nM)9.6N/AN/ADetails
VatalanibVascular endothelial growth factor receptor 2Kd (nM)62N/AN/ADetails
VatalanibVascular endothelial growth factor receptor 3Kd (nM)330N/AN/ADetails