Tuesday, November 20, 2018

Covalent Docking Identifies a Potent and Selective MKK7 Inhibitor [@london_lab]

Amit Shraga, Evgenia Olshvang, Natalia Davidzohn, Payam Khoshkenar, Nicolas Germain, Khriesto Shurrush, Silvia Carvalho, Liat Avram, Shira Albeck, Tamar Unger, Bruce Lefker, Chakrapani Subramanyam, Robert L. Hudkins, Amir Mitchell, Ziv Shulman, Takayoshi Kinoshita, Nir London,
Covalent Docking Identifies a Potent and Selective MKK7 Inhibitor,
Cell Chemical Biology, 2018

DOI: 10.1016/j.chembiol.2018.10.011

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.

Discovery and Characterization of a Novel Series of Chloropyrimidines as Covalent Inhibitors of the Kinase MSK1

Adrian Hall, Jan Abendroth, Madison J. Bolejack, Tom Ceska, Sylvie Dell’Aiera, Victoria Ellis, David Fox, Cyril François, Muigai M. Muruthi,...