Rational design of inhibitors that bind to inactive kinase conformations.

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Liu Y, Gray NS

Rational design of inhibitors that bind to inactive kinase conformations.

Nat Chem Biol. 2006 Jul;2(7):358-64.

PubMed ID
16783341 [ View in PubMed
]
Abstract

The majority of kinase inhibitors that have been developed so far--known as type I inhibitors--target the ATP binding site of the kinase in its active conformation, in which the activation loop is phosphorylated. Recently, crystal structures of inhibitors such as imatinib (STI571), BIRB796 and sorafenib (BAY43-9006)--known as type II inhibitors--have revealed a new binding mode that exploits an additional binding site immediately adjacent to the region occupied by ATP. This pocket is made accessible by an activation-loop rearrangement that is characteristic of kinases in an inactive conformation. Here, we present a structural analysis of binding modes of known human type II inhibitors and demonstrate that they conform to a pharmacophore model that is currently being used to design a new generation of kinase inhibitors.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
1-(5-Tert-Butyl-2-Methyl-2h-Pyrazol-3-Yl)-3-(4-Chloro-Phenyl)-UreaMitogen-activated protein kinase 14Kd (nM)1160N/AN/ADetails
3-FLUORO-5-MORPHOLIN-4-YL-N-[1-(2-PYRIDIN-4-YLETHYL)-1H-INDOL-6-YL]BENZAMIDEMitogen-activated protein kinase 14IC 50 (nM)340N/AN/ADetails
ImatinibPlatelet-derived growth factor receptor betaIC 50 (nM)386N/AN/ADetails
ImatinibTyrosine-protein kinase ABL1Ki (nM)37N/AN/ADetails
ImatinibTyrosine-protein kinase ABL1Ki (nM)7000N/AN/ADetails
ImatinibTyrosine-protein kinase ABL1IC 50 (nM)188N/AN/ADetails
SorafenibFibroblast growth factor receptor 1IC 50 (nM)580N/AN/ADetails
SorafenibPlatelet-derived growth factor receptor betaIC 50 (nM)57N/AN/ADetails
SorafenibReceptor-type tyrosine-protein kinase FLT3IC 50 (nM)58N/AN/ADetails
SorafenibSerine/threonine-protein kinase B-rafIC 50 (nM)22N/AN/ADetails
SorafenibVascular endothelial growth factor receptor 2IC 50 (nM)90N/AN/ADetails