2. Academic Validation
  3. Discovery of potent and selective covalent inhibitors of JNK

Discovery of potent and selective covalent inhibitors of JNK

  • Chem Biol. 2012 Jan 27;19(1):140-54. doi: 10.1016/j.chembiol.2011.11.010.
Tinghu Zhang 1,  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
Affiliations

Affiliation

  • 1 Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
PMID: 22284361 DOI: 10.1016/j.chembiol.2011.11.010
Abstract

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 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.

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