Discovery of potent and selective covalent inhibitors of JNK

Tinghu Zhang, Francisco Inesta-Vaquera, Mario Niepel, Jianming Zhang, Scott B. Ficarro, Thomas Machleidt, Ting Xie, Jarrod A. Marto, NamDoo Kim, Taebo Sim, John D. Laughlin, Hajeung Park, Philip V. LoGrasso, Matt Patricelli, Tyzoon K. Nomanbhoy, Peter K. Sorger, Dario R. Alessi, Nathanael S. Gray

    Research output: Contribution to journalArticlepeer-review

    260 Citations (Scopus)


    The 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 angstrom 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.

    Original languageEnglish
    Pages (from-to)140-154
    Number of pages15
    JournalChemistry & Biology
    Issue number1
    Publication statusPublished - 27 Jan 2012


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