Article

Discovery of Potent and Selective Covalent Inhibitors of JNK

Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Chemistry & biology (Impact Factor: 6.65). 01/2012; 19(1):140-54. DOI: 10.1016/j.chembiol.2011.11.010
Source: PubMed

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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    • "Therefore, we sought to test whether Tead-AP1 cooperation depends on JNK activity in cancer cells. We used a recently developed, highly specific JNK inhibitor, JNK-IN-8 (Zhang et al., 2012), and showed that JNK-IN-8 treatment of HCT116 or A549 cells was able to effectively block c-Jun phosphorylation but not large tumor suppressor kinase (Lats)mediated YAP phosphorylation (Figure 4A) (data not shown). JNK inhibition also did not alter YAP cellular localization or the expression of the YAP target genes, CTGF and ANKRD1 (Fig- ure 4B; Figure S3). "
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