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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    • " 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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