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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Available from: Mario Niepel, Sep 29, 2015
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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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    Chemistry & biology 11/2014; 21(11):1433-1443. DOI:10.1016/j.chembiol.2014.09.007 · 6.65 Impact Factor
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    • "These small - molecule inhibitors form a covalent bond with a nucleophilic cysteine residue within the kinase ATP - binding pocket , thus irreversibly inactivating the target kinase . An effort undertaken by Gray and colleagues ( Zhang et al , 2012 ) , aimed at developing irreversible covalent inhibitors of JNK1 / 2 / 3 , serendi - pitously led to the discovery of a covalent kinase inhibitor of IRAK1 . KINOMEscan profiling revealed that the JNK - IN - 7 phenylamino - pyrimidine tool compound not only interacts with JNK1 / 2 / 3 , but also IRAK1 , exhibiting an enzymatic IC 50 of B10 nM . "
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    • "After attachment (2 h), the medium was removed and the hepatocytes were incubated (22 h) in maintenance medium (DMEM (4.5g/L glucose) supplemented with 10% FBS, 0.2% BSA, 2mM sodium pyruvate, 2% Pen/Strep, 0.1 µM dexamethasone, 1nM insulin). When indicated, the hepatocytes were incubated (16 h) with PPARα agonists (50 µM WY14043 (Sigma) or 100 µM Fenofibrate (Sigma)) or antagonists (10 µM GW6471 (Sigma) or 20 µM MK886 (Santa Cruz)) or the JNK inhibitor (E)-3-(4-(dimethylamino)but-2-enamido)-N-(3-methyl-4-((4-(pyridin-3- yl)pyrimidin-2-yl)amino)phenyl)benzamide (JNK-in-8; EMD-Millipore; Zhang et al. (2012)). The drugs were dissolved in DMSO; control studies were performed by addition of vehicle (DMSO) alone. "
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