TY - JOUR
T1 - Covalent Docking Identifies a Potent and Selective MKK7 Inhibitor
AU - Olshvang, Evgenia
AU - Davidzohn, Natalia
AU - Khoshkenar, Payam
AU - Germain, Nicolas
AU - Shurrush, Khriesto
AU - Avram, Liat
AU - Albeck, Shira
AU - Unger, Tamar
AU - Lefker, Bruce
AU - Subramanyam, Chakrapani
AU - Hudkins, Robert L.
AU - Mitchell, Amir
AU - Shulman, Ziv
AU - Kinoshita, Takayoshi
AU - London, Nir
N1 - N.L. is the incumbent of the Alan and Laraine Fischer Career Development Chair; N.L. would like to acknowledge funding from the Israel Science Foundation (grant no. 1097/16), the German-Israeli Foundation (I-2483-302.5/2017), and Teva National Network of Neuroscience. We thank Prof. Roger Davis for generously providing us with the 3T3 WT, MKK7−/−, and MKK4/7−/− cell lines (Tournier et al., 2001), and Dr. Haim Barr and Dr. Christian Dubiella for critical reading of the manuscript. This work was performed in part using synchrotron beamlines, SPring-8 BL44XU (2017A6717) under the cooperative research program of the Institute for Protein Research, Osaka University, Photon Factory BL17A (2016G033), and Aichi Synchrotron BL2S1 (2017N3003).
PY - 2019/1/17
Y1 - 2019/1/17
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85059791362&partnerID=8YFLogxK
U2 - 10.1016/j.chembiol.2018.10.011
DO - 10.1016/j.chembiol.2018.10.011
M3 - مقالة
SN - 2451-9456
VL - 26
SP - 98
EP - 108
JO - Cell Chemical Biology
JF - Cell Chemical Biology
IS - 1
ER -