Discovery of Potent and Selective Covalent Inhibitors of JNK

SummaryThe mitogen-activated kinases JNK1/2/3 are key enzymes in signaling modules that transduce and integrate extracellular stimuli into coordinated cellular response. Here, we report the discovery of irreversible inhibitors of JNK1/2/3. We describe two JNK3 cocrystal structures at 2.60 and 2.97 Å resolution that show the compounds form covalent bonds with a conserved cysteine residue. JNK-IN-8 is a selective JNK inhibitor that inhibits phosphorylation of c-Jun, a direct substrate of JNK, in cells exposed to submicromolar drug in a manner that depends on covalent modification of the conserved cysteine residue. Extensive biochemical, cellular, and pathway-based profiling establish the selectivity of JNK-IN-8 for JNK and suggests that the compound will be broadly useful as a pharmacological probe of JNK-dependent signal transduction. Potential lead compounds have also been identified for kinases, including IRAK1, PIK3C3, PIP4K2C, and PIP5K3.

Graphical AbstractFigure optionsDownload high-quality image (383 K)Download as PowerPoint slideHighlights
► JNK inhibitors have been designed that target a conserved cysteine residue
► JNK-IN-8 is a highly selective JNK inhibitor based on multiple profiling strategies
► Covalent formation is crucial for both high potency and high specificity
► JNK-IN-8 inhibits c-Jun phosphorylation at submicromolar concentrations in cells