Covalent Docking Identifies a Potent and Selective MKK7 Inhibitor

UMMS Affiliation

Program for Systems Biology; Program in Molecular Medicine

Publication Date


Document Type



Biochemistry | Cell Biology | Cellular and Molecular Physiology | Enzymes and Coenzymes | Investigative Techniques | Molecular Biology | Systems Biology | Therapeutics


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 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 that 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 an on-target effect using knockout cell lines. Lastly, we show that 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.


DOCKovalent, JNK, MAPK, MKK7, covalent docking, covalent inhibitor, kinase inhibitors, virtual screening

DOI of Published Version



Cell Chem Biol. 2018 Oct 24. pii: S2451-9456(18)30344-1. doi: 10.1016/j.chembiol.2018.10.011. [Epub ahead of print] Link to article on publisher's site

Journal/Book/Conference Title

Cell chemical biology


Full author list omitted for brevity. For the full list of authors, see article.

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