Covalent Docking Identifies a Potent and Selective MKK7 Inhibitor. Issue 1 (17th January 2019)

• Record Type: Journal Article
• Authors: Shraga, Amit; Olshvang, Evgenia; Davidzohn, Natalia; Khoshkenar, Payam; Germain, Nicolas; Shurrush, Khriesto; Carvalho, Silvia; Avram, Liat; Albeck, Shira; Unger, Tamar; Lefker, Bruce; Subramanyam, Chakrapani; Hudkins, Robert L.; Mitchell, Amir; Shulman, Ziv; Kinoshita, Takayoshi; London, Nir
• Is Part Of: Cell chemical biology. Volume 26:Issue 1(2019)
• Page Start: 98
• Page End: 108.e5
• Publication Date: 2019-01-17
• Subjects: covalent docking -- DOCKovalent -- MKK7 -- covalent inhibitor -- JNK -- MAPK -- virtual screening -- kinase inhibitors; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2018.10.011
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: 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. Graphical Abstract: Highlights: Covalent docking accurately predicts a covalent MKK7 inhibitor Inhibitors are potent in vitro and block JNK phosphorylation in cells MKK7 inhibitors are selective across the kinome and proteome MKK7 inhibitors block primary B cell activation in response to LPS Abstract : Shraga et al. use covalent docking to identify covalent inhibitors for MKK7. Crystallography validated the predicted binding pose, and optimization led to potent inhibitors that block JNK (MKK7's substrate) phosphorylation in cells. The compounds are selective and as such can serve as tools to further study MKK7.