A quantitative analysis of kinase inhibitor selectivity.

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Karaman MW, Herrgard S, Treiber DK, Gallant P, Atteridge CE, Campbell BT, Chan KW, Ciceri P, Davis MI, Edeen PT, Faraoni R, Floyd M, Hunt JP, Lockhart DJ, Milanov ZV, Morrison MJ, Pallares G, Patel HK, Pritchard S, Wodicka LM, Zarrinkar PP

A quantitative analysis of kinase inhibitor selectivity.

Nat Biotechnol. 2008 Jan;26(1):127-32. doi: 10.1038/nbt1358.

PubMed ID
18183025 [ View in PubMed
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Abstract

Kinase inhibitors are a new class of therapeutics with a propensity to inhibit multiple targets. The biological consequences of multi-kinase activity are poorly defined, and an important step toward understanding the relationship between selectivity, efficacy and safety is the exploration of how inhibitors interact with the human kinome. We present interaction maps for 38 kinase inhibitors across a panel of 317 kinases representing >50% of the predicted human protein kinome. The data constitute the most comprehensive study of kinase inhibitor selectivity to date and reveal a wide diversity of interaction patterns. To enable a global analysis of the results, we introduce the concept of a selectivity score as a general tool to quantify and differentiate the observed interaction patterns. We further investigate the impact of panel size and find that small assay panels do not provide a robust measure of selectivity.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
AlvocidibCyclin-dependent kinase 2Kd (nM)550N/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)>10000N/AN/ADetails
AlvocidibEpidermal growth factor receptorKd (nM)2300N/AN/ADetails
AlvocidibEpidermal growth factor receptorKd (nM)1400N/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
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)1.1N/AN/ADetails
DasatinibTyrosine-protein kinase ABL1Kd (nM)1.2N/AN/ADetails
DasatinibTyrosine-protein kinase ABL1Kd (nM)0.72N/AN/ADetails
DasatinibTyrosine-protein kinase ABL1Kd (nM)590N/AN/ADetails
DasatinibTyrosine-protein kinase ABL1Kd (nM)0.96N/AN/ADetails
DasatinibTyrosine-protein kinase ABL1Kd (nM)0.53N/AN/ADetails
DasatinibTyrosine-protein kinase ABL1Kd (nM)2.1N/AN/ADetails
DasatinibTyrosine-protein kinase ABL2Kd (nM)0.17N/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)0.37N/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
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)19N/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)21N/AN/ADetails
ImatinibTyrosine-protein kinase ABL1Kd (nM)8.5N/AN/ADetails
ImatinibTyrosine-protein kinase ABL1Kd (nM)35N/AN/ADetails
ImatinibTyrosine-protein kinase ABL1Kd (nM)>10000N/AN/ADetails
ImatinibTyrosine-protein kinase ABL1Kd (nM)12N/AN/ADetails
ImatinibTyrosine-protein kinase ABL1Kd (nM)77N/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
LapatinibReceptor tyrosine-protein kinase erbB-2Kd (nM)7N/AN/ADetails
NeflamapimodMitogen-activated protein kinase 14Kd (nM)2.8N/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
SeliciclibCasein kinase I isoform epsilonKd (nM)320N/AN/ADetails
SeliciclibCyclin-dependent kinase 2Kd (nM)3400N/AN/ADetails
SeliciclibCyclin-dependent kinase 7Kd (nM)1800N/AN/ADetails
SeliciclibCyclin-dependent kinase 9Kd (nM)>10000N/AN/ADetails
SeliciclibMitogen-activated protein kinase 1Kd (nM)>10000N/AN/ADetails
SeliciclibMitogen-activated protein kinase 3Kd (nM)>10000N/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
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
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
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)2N/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)0.47N/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
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
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
TofacitinibNon-receptor tyrosine-protein kinase TYK2Kd (nM)620N/AN/ADetails
TofacitinibTyrosine-protein kinase JAK2Kd (nM)5N/AN/ADetails
TofacitinibTyrosine-protein kinase JAK3Kd (nM)2.2N/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
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
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