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


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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    • "Interestingly, DAPT also prevented NGFmediated activation of the NF-kB pathway in these cells, whereas TAPI had no effect (Fig. 6C), complementary to the observed effects on cell death. Moreover, the activation of caspase-3 by NGF in the presence of DAPT could be abolished by JNK-IN-8 (Fig. 6D), a specific JNK inhibitor (Zhang et al., 2012), indicating the involvement of the JNK pathway in the activation of caspase-3 in CGNs. Taken together, these results suggest that deficient c-cleavage after a-cleavage, but not proteolytic processing per se, of p75 NTR prevents activation of NF-kB by NGF and allows the induction of cell death in CGNs. "
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    • " the amino group for the binding was also highlighted in two independent SAR studies . The first demon - strated that the replacement of the nitrogen with another atom , such as oxygen , by creating an ether function ( compound 16 versus compound 25 in Figure 4 and Table 1 , respectively ) induced a complete loss of the activity of the inhibitor ( Zhang et al . , 2012 ) . In the same way , a second SAR study showed that the addition of a substituent replacing the hydrogen atom on the amino group leads to a complete loss of activity ( com - pound 30 compared with compounds 29 and 31 ) ( Liu et al . , 2007 ) or to a change in the orientation and the binding mode of the compound ( compound 28 compared w"
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