A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases.

Article Details


Fedorov O, Marsden B, Pogacic V, Rellos P, Muller S, Bullock AN, Schwaller J, Sundstrom M, Knapp S

A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases.

Proc Natl Acad Sci U S A. 2007 Dec 18;104(51):20523-8. Epub 2007 Dec 11.

PubMed ID
18077363 [ View in PubMed

Protein kinases play a pivotal role in cell signaling, and dysregulation of many kinases has been linked to disease development. A large number of kinase inhibitors are therefore currently under investigation in clinical trials, and so far seven inhibitors have been approved as anti-cancer drugs. In addition, kinase inhibitors are widely used as specific probes to study cell signaling, but systematic studies describing selectivity of these reagents across a panel of diverse kinases are largely lacking. Here we evaluated the specificity of 156 validated kinase inhibitors, including inhibitors used in clinical trials, against 60 human Ser/Thr kinases using a thermal stability shift assay. Our analysis revealed many unexpected cross-reactivities for inhibitors thought to be specific for certain targets. We also found that certain combinations of active-site residues in the ATP-binding site correlated with the detected ligand promiscuity and that some kinases are highly sensitive to inhibition using diverse chemotypes, suggesting them as preferred intervention points. Our results uncovered also inhibitor cross-reactivities that may lead to alternate clinical applications. For example, LY333'531, a PKCbeta inhibitor currently in phase III clinical trials, efficiently inhibited PIM1 kinase in our screen, a suggested target for treatment of leukemia. We determined the binding mode of this inhibitor by x-ray crystallography and in addition showed that LY333'531 induced cell death and significantly suppressed growth of leukemic cells from acute myeloid leukemia patients.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
2-tert-butyl-9-fluoro-1,6-dihydrobenzo[h]imidazo[4,5-f]isoquinolin-7-oneNon-receptor tyrosine-protein kinase TYK2IC 50 (nM)1N/AN/ADetails
2-tert-butyl-9-fluoro-1,6-dihydrobenzo[h]imidazo[4,5-f]isoquinolin-7-oneTyrosine-protein kinase JAK2IC 50 (nM)1N/AN/ADetails
2-tert-butyl-9-fluoro-1,6-dihydrobenzo[h]imidazo[4,5-f]isoquinolin-7-oneTyrosine-protein kinase JAK3IC 50 (nM)5N/AN/ADetails
4-[3-Hydroxyanilino]-6,7-DimethoxyquinazolineCyclin-dependent kinase 2IC 50 (nM)1000N/AN/ADetails
5-(2-PHENYLPYRAZOLO[1,5-A]PYRIDIN-3-YL)-1H-PYRAZOLO[3,4-C]PYRIDAZIN-3-AMINEMitogen-activated protein kinase 1Ki (nM)310N/AN/ADetails
AlsterpaulloneGlycogen synthase kinase-3 betaIC 50 (nM)20N/AN/ADetails
AR-AO-14418Glycogen synthase kinase-3 betaIC 50 (nM)104N/AN/ADetails
AR-AO-14418Glycogen synthase kinase-3 betaKi (nM)38N/AN/ADetails
Indirubin-3'-monoximeCyclin-dependent kinase 5 activator 1IC 50 (nM)100N/AN/ADetails
Indirubin-3'-monoximeGlycogen synthase kinase-3 betaIC 50 (nM)22N/AN/ADetails
PyrazolanthroneMitogen-activated protein kinase 10IC 50 (nM)90N/AN/ADetails
PyrazolanthroneMitogen-activated protein kinase 8IC 50 (nM)40N/AN/ADetails
SeliciclibMitogen-activated protein kinase 1IC 50 (nM)14000N/AN/ADetails
SeliciclibMitogen-activated protein kinase 3IC 50 (nM)34000N/AN/ADetails