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

265 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 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 and Biology
Issue number1
Publication statusPublished - 2012 Jan 27

Bibliographical note

Funding Information:
Funding was provided by NIH U54 HG006097, NIH 1RC2HG005693, 5 RCD HG005693-02, 5 RC2 CA148164-02, 1 U54 HG 006907-01, NS057153-04, and American Skin Association, Milstein Innovation Award. Thanks to Kendall Nettles for help with the determination of JNK3 inhibitor structures. Thanks to the Medical Research Council UK, the Wellcome Trust, and the pharmaceutical companies supporting the Division of Signal Transduction Therapy Unit (AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck KgaA, and Pfizer). Special thanks to Lili Zhou for assistance with high-throughput microscopy and Eddy Goh and Philip Cohen for developing the cellular IRAK1 assays and helpful discussions.

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry


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