Zhang, Tinghu Inesta-Vaquera, Francisco Niepel, Mario Zhang, Jianming Ficarro, Scott B. Machleidt, Thomas Xie, Ting Marto, Jarrod A. Kim, NamDoo Sim, Taebo Laughlin, John D. Park, Hajeung LoGrasso, Philip V. Patricelli, Matt Nomanbhoy, Tyzoon K. Sorger, Peter K. Alessi, Dario R. Gray, Nathanael S. 2024-01-20T15:33:05Z 2024-01-20T15:33:05Z 2021-09-05 2012-01-27 1074-5521 https://pubs.kist.re.kr/handle/201004/129630 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. English CELL PRESS N-TERMINAL-KINASE INSULIN-RECEPTOR SUBSTRATE-1 ACTIVATED PROTEIN-KINASES TYROSINE KINASE SIGNAL-TRANSDUCTION CYTOKINE PRODUCTION IN-VIVO MAP PHOSPHORYLATION PATHWAYS Discovery of Potent and Selective Covalent Inhibitors of JNK Article 10.1016/j.chembiol.2011.11.010 1 CHEMISTRY & BIOLOGY, v.19, no.1, pp.140 - 154 CHEMISTRY & BIOLOGY 19 1 140 154 scie scopus 000300074500014 2-s2.0-84863056297 Biochemistry & Molecular Biology Biochemistry & Molecular Biology Article N-TERMINAL-KINASE INSULIN-RECEPTOR SUBSTRATE-1 ACTIVATED PROTEIN-KINASES TYROSINE KINASE SIGNAL-TRANSDUCTION CYTOKINE PRODUCTION IN-VIVO MAP PHOSPHORYLATION PATHWAYS JNK