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Cell Chem Biol. 2019 Jan 17;26(1):98-108.e5. doi: 10.1016/j.chembiol.2018.10.011. Epub 2018 Nov 15.

Covalent Docking Identifies a Potent and Selective MKK7 Inhibitor.

Author information

1
Department of Organic Chemistry, The Weizmann Institute of Science, Rehovot 76100, Israel.
2
Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel.
3
Program for Systems Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
4
Maurice and Vivienne Wohl Institute for Drug Discovery, Nancy and Stephen Grand Israel National Center for Personalized Medicine, The Weizmann Institute of Science, Rehovot 76100, Israel.
5
Department of Chemical Research Support, The Weizmann Institute of Science, Rehovot 76100, Israel.
6
Structural Proteomics Unit, Department of Life Sciences Core Facilities, The Weizmann Institute of Science, Rehovot 76100, Israel.
7
Maurice and Vivienne Wohl Institute for Drug Discovery, Nancy and Stephen Grand Israel National Center for Personalized Medicine, The Weizmann Institute of Science, Rehovot 76100, Israel; Pfizer, Research and Development, USA.
8
Specialty Research & Development, Teva Pharmaceuticals, Inc., West Chester, PA 19380, USA.
9
Graduate School of Science, Osaka Prefecture University, Osaka 599-8531, Japan.
10
Department of Organic Chemistry, The Weizmann Institute of Science, Rehovot 76100, Israel. Electronic address: nir.london@weizmann.ac.il.

Abstract

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.

KEYWORDS:

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

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