Discovery of Potent and Selective Covalent Inhibitors of JNK
- 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; 심태보; John D. Laughlin; Hajeung Park; Philip V. LoGrasso; Matt Patricelli; Tyzoon K. Nomanbhoy; Peter K. Sorger; Dario R. Alessi; Nathanael S. Gray
- Issue Date
- Chemistry & biology
- VOL 19, NO 1, 140-154
- 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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