Inflammatory Signaling by NOD-RIPK2 Is Inhibited by Clinically Relevant Type II Kinase Inhibitors
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Inflammatory Signaling by NOD-RIPK2 Is Inhibited by Clinically Relevant Type II Kinase Inhibitors. / Canning, Peter; Ruan, Qui; Schwerd, Tobias; Hrdinka, Matous; Maki, Jenny L; Saleh, Danish; Suebsuwong, Chalada; Ray, Soumya; Brennan, Paul E; Cuny, Gregory D; Uhlig, Holm H; Gyrd-Hansen, Mads; Degterev, Alexei; Bullock, Alex N.
In: Cell Chemical Biology, Vol. 22, No. 9, 17.09.2015, p. 1174-84.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Inflammatory Signaling by NOD-RIPK2 Is Inhibited by Clinically Relevant Type II Kinase Inhibitors
AU - Canning, Peter
AU - Ruan, Qui
AU - Schwerd, Tobias
AU - Hrdinka, Matous
AU - Maki, Jenny L
AU - Saleh, Danish
AU - Suebsuwong, Chalada
AU - Ray, Soumya
AU - Brennan, Paul E
AU - Cuny, Gregory D
AU - Uhlig, Holm H
AU - Gyrd-Hansen, Mads
AU - Degterev, Alexei
AU - Bullock, Alex N
N1 - Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.
PY - 2015/9/17
Y1 - 2015/9/17
N2 - RIPK2 mediates pro-inflammatory signaling from the bacterial sensors NOD1 and NOD2, and is an emerging therapeutic target in autoimmune and inflammatory diseases. We observed that cellular RIPK2 can be potently inhibited by type II inhibitors that displace the kinase activation segment, whereas ATP-competitive type I inhibition was only poorly effective. The most potent RIPK2 inhibitors were the US Food and Drug Administration-approved drugs ponatinib and regorafenib. Their mechanism of action was independent of NOD2 interaction and involved loss of downstream kinase activation as evidenced by lack of RIPK2 autophosphorylation. Notably, these molecules also blocked RIPK2 ubiquitination and, consequently, inflammatory nuclear factor κB signaling. In monocytes, the inhibitors selectively blocked NOD-dependent tumor necrosis factor production without affecting lipopolysaccharide-dependent pathways. We also determined the first crystal structure of RIPK2 bound to ponatinib, and identified an allosteric site for inhibitor development. These results highlight the potential for type II inhibitors to treat indications of RIPK2 activation as well as inflammation-associated cancers.
AB - RIPK2 mediates pro-inflammatory signaling from the bacterial sensors NOD1 and NOD2, and is an emerging therapeutic target in autoimmune and inflammatory diseases. We observed that cellular RIPK2 can be potently inhibited by type II inhibitors that displace the kinase activation segment, whereas ATP-competitive type I inhibition was only poorly effective. The most potent RIPK2 inhibitors were the US Food and Drug Administration-approved drugs ponatinib and regorafenib. Their mechanism of action was independent of NOD2 interaction and involved loss of downstream kinase activation as evidenced by lack of RIPK2 autophosphorylation. Notably, these molecules also blocked RIPK2 ubiquitination and, consequently, inflammatory nuclear factor κB signaling. In monocytes, the inhibitors selectively blocked NOD-dependent tumor necrosis factor production without affecting lipopolysaccharide-dependent pathways. We also determined the first crystal structure of RIPK2 bound to ponatinib, and identified an allosteric site for inhibitor development. These results highlight the potential for type II inhibitors to treat indications of RIPK2 activation as well as inflammation-associated cancers.
KW - Amino Acid Sequence
KW - Animals
KW - Cells, Cultured
KW - Humans
KW - Imidazoles/chemistry
KW - Inflammation/metabolism
KW - Models, Molecular
KW - Molecular Sequence Data
KW - Nod1 Signaling Adaptor Protein/antagonists & inhibitors
KW - Nod2 Signaling Adaptor Protein/antagonists & inhibitors
KW - Protein Binding
KW - Protein Kinase Inhibitors/chemistry
KW - Pyridazines/chemistry
KW - Receptor-Interacting Protein Serine-Threonine Kinase 2/antagonists & inhibitors
KW - Sf9 Cells
KW - Signal Transduction/drug effects
KW - Ubiquitination/drug effects
U2 - 10.1016/j.chembiol.2015.07.017
DO - 10.1016/j.chembiol.2015.07.017
M3 - Journal article
C2 - 26320862
VL - 22
SP - 1174
EP - 1184
JO - Chemistry and Biology
JF - Chemistry and Biology
SN - 2451-9456
IS - 9
ER -
ID: 280718675