TY - JOUR
T1 - Discovery of potent and selective covalent inhibitors of JNK
AU - Zhang, Tinghu
AU - Inesta-Vaquera, Francisco
AU - Niepel, Mario
AU - Zhang, Jianming
AU - Ficarro, Scott B.
AU - MacHleidt, Thomas
AU - Xie, Ting
AU - Marto, Jarrod A.
AU - Kim, Namdoo
AU - Sim, Taebo
AU - Laughlin, John D.
AU - Park, Hajeung
AU - Lograsso, Philip V.
AU - Patricelli, Matt
AU - Nomanbhoy, Tyzoon K.
AU - Sorger, Peter K.
AU - Alessi, Dario R.
AU - Gray, Nathanael S.
N1 - 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.
PY - 2012/1/27
Y1 - 2012/1/27
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84863056297&partnerID=8YFLogxK
U2 - 10.1016/j.chembiol.2011.11.010
DO - 10.1016/j.chembiol.2011.11.010
M3 - Article
C2 - 22284361
AN - SCOPUS:84863056297
SN - 2451-9448
VL - 19
SP - 140
EP - 154
JO - Cell Chemical Biology
JF - Cell Chemical Biology
IS - 1
ER -