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Discovery of potent and selective covalent inhibitors of JNK

Discovery of potent and selective covalent inhibitors of JNK

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  • 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

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


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.



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