Inflammatory Signaling by NOD-RIPK2 Is Inhibited by Clinically Relevant Type II Kinase Inhibitors

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

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

Harvard

Canning, P, Ruan, Q, Schwerd, T, Hrdinka, M, Maki, JL, Saleh, D, Suebsuwong, C, Ray, S, Brennan, PE, Cuny, GD, Uhlig, HH, Gyrd-Hansen, M, Degterev, A & Bullock, AN 2015, 'Inflammatory Signaling by NOD-RIPK2 Is Inhibited by Clinically Relevant Type II Kinase Inhibitors', Cell Chemical Biology, vol. 22, no. 9, pp. 1174-84. https://doi.org/10.1016/j.chembiol.2015.07.017

APA

Canning, P., Ruan, Q., Schwerd, T., Hrdinka, M., Maki, J. L., Saleh, D., Suebsuwong, C., Ray, S., Brennan, P. E., Cuny, G. D., Uhlig, H. H., Gyrd-Hansen, M., Degterev, A., & Bullock, A. N. (2015). Inflammatory Signaling by NOD-RIPK2 Is Inhibited by Clinically Relevant Type II Kinase Inhibitors. Cell Chemical Biology, 22(9), 1174-84. https://doi.org/10.1016/j.chembiol.2015.07.017

Vancouver

Canning P, Ruan Q, Schwerd T, Hrdinka M, Maki JL, Saleh D et al. Inflammatory Signaling by NOD-RIPK2 Is Inhibited by Clinically Relevant Type II Kinase Inhibitors. Cell Chemical Biology. 2015 Sep 17;22(9):1174-84. https://doi.org/10.1016/j.chembiol.2015.07.017

Author

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. / Inflammatory Signaling by NOD-RIPK2 Is Inhibited by Clinically Relevant Type II Kinase Inhibitors. In: Cell Chemical Biology. 2015 ; Vol. 22, No. 9. pp. 1174-84.

Bibtex

@article{4470d22435e3491da0837ed03f3d0b6a,
title = "Inflammatory Signaling by NOD-RIPK2 Is Inhibited by Clinically Relevant Type II Kinase Inhibitors",
abstract = "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.",
keywords = "Amino Acid Sequence, Animals, Cells, Cultured, Humans, Imidazoles/chemistry, Inflammation/metabolism, Models, Molecular, Molecular Sequence Data, Nod1 Signaling Adaptor Protein/antagonists & inhibitors, Nod2 Signaling Adaptor Protein/antagonists & inhibitors, Protein Binding, Protein Kinase Inhibitors/chemistry, Pyridazines/chemistry, Receptor-Interacting Protein Serine-Threonine Kinase 2/antagonists & inhibitors, Sf9 Cells, Signal Transduction/drug effects, Ubiquitination/drug effects",
author = "Peter Canning and Qui Ruan and Tobias Schwerd and Matous Hrdinka and Maki, {Jenny L} and Danish Saleh and Chalada Suebsuwong and Soumya Ray and Brennan, {Paul E} and Cuny, {Gregory D} and Uhlig, {Holm H} and Mads Gyrd-Hansen and Alexei Degterev and Bullock, {Alex N}",
note = "Copyright {\textcopyright} 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.",
year = "2015",
month = sep,
day = "17",
doi = "10.1016/j.chembiol.2015.07.017",
language = "English",
volume = "22",
pages = "1174--84",
journal = "Chemistry and Biology",
issn = "2451-9456",
publisher = "Elsevier",
number = "9",

}

RIS

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