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Covalent docking identifies a potent and selective MKK7 inhibitor
2Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
3Program for Systems Biology, University of Massachusetts Medical School, Worcester, MA, USA
4The Nancy and Stephen Grand Israel National Center for Personalized Medicine, and the Maurice and Vivienne Wohl Institute for Drug Discovery, Weizmann Institute of Science, Rehovot, Israel
5Department of Chemical Research Support, Weizmann Institute of Science, Rehovot, Israel
6Department of Life Sciences Core Facilities, Structural Proteomics Unit, Weizmann Institute of Science, Rehovot, Israel
7Research and Development, Pfizer, Boston, MA, USA
8Specialty Research & Development, Teva Pharmaceuticals, Inc., Pennsylvania, West Chester, PA, USA
9Graduate School of Science, Osaka Prefecture University, Osaka, Japan
The c-Jun NH2-terminal Kinase (JNK) signaling pathway is central to the cell response to stress, inflammatory signals and toxins. While selective inhibitors are known for JNKs and for various upstream MAP3Ks, no selective inhibitor is reported for MKK7 - one of two direct MAP2Ks that activate JNK. Here, using covalent virtual screening, we identify the first selective MKK7 covalent inhibitors. We optimized these compounds to low-micromolar inhibitors of JNK phosphorylation in cells. The crystal structure of a lead compound bound to MKK7, demonstrated the binding mode was correctly predicted by docking. We asserted the selectivity of our inhibitors on a proteomic level and against a panel of 76 kinases, and validated on-target effect using knockout cell-lines. Lastly, we show the inhibitors block activation of primary mouse B cells by lipopolysaccharide. These MKK7 tool compounds will enable better investigation of JNK signaling and may serve as starting points for therapeutics.
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