Receptor-interacting protein kinase 2 (RIPK2) and nucleotide-binding oligomerization domain (NOD) cell signaling inhibitors based on a 3,5-diphenyl-2-aminopyridine scaffold

Suebsuwong, Chalada; Dai, Bing; Pinkas, Daniel; Duddupudi, Anantha L.; Li, Li; Bufton, J.C.; Schlicher, Lisa; Gyrd‐Hansen, Mads; Hu, Ming; Bullock, Alex N.; Degterev, Alexei; Cuny, Gregory D.

doi:10.1016/j.ejmech.2020.112417

Cited by 14 publications

(11 citation statements)

References 43 publications

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“…These RIPK2 inhibitors are believed to inhibit kinase activity of RIPK2 (Hollenbach et al, 2005;Tigno-Aranjuez et al, 2014;Nachbur et al, 2015;Salla et al, 2018). However, recent studies provide evidence that kinase activity of RIPK2 is dispensable for NOD2 signaling, and that RIPK2 inhibitors inhibit the polyubiquitination of RIPK2 through disrupting the interaction between RIPK2 and XIAP (Goncharov et al, 2018;Hrdinka et al, 2018;Suebsuwong et al, 2020). Therefore, it is likely that RIPK2 inhibitors prevent experimental colitis through the suppression of polyubiquitination of RIPK2.…”

Section: Recent Progress In Receptor-interacting Serine/ Threonine Kinase 2 Inhibitorsmentioning

confidence: 99%

RIPK2 as a New Therapeutic Target in Inflammatory Bowel Diseases

et al. 2021

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Inflammatory bowel diseases (IBDs) are becoming more frequent worldwide. A significant fraction of patients with IBD are refractory to various types of therapeutic biologics and small molecules. Therefore, identification of novel therapeutic targets in IBD is required. Receptor-interacting serine/threonine kinase 2 (RIPK2), also known as receptor-interacting protein 2 (RIP2), is a downstream signaling molecule for nucleotide-binding oligomerization domain 1 (NOD1), NOD2, and Toll-like receptors (TLRs). RIPK2 is expressed in antigen-presenting cells, such as dendritic cells and macrophages. Recognition of microbe-associated molecular patterns by NOD1, NOD2, and TLRs leads to the interaction between RIPK2 and these innate immune receptors, followed by the release of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-12/23p40 through the activation of nuclear factor kappa B and mitogen-activated protein kinases. Thus, activation of RIPK2 plays a critical role in host defense against microbial infections. Recent experimental and clinical studies have provided evidence that activation of RIPK2 is involved in the development of autoimmune diseases, especially IBDs. In addition, the colonic mucosa of patients with IBD exhibits enhanced expression of RIPK2 and associated signaling molecules. Furthermore, the blockage of RIPK2 activation ameliorates the development of experimental murine colitis. Thus, activation of RIPK2 underlies IBD immunopathogenesis. In this review, we attempt to clarify the roles played by RIPK2 in the development of IBD by focusing on its associated signaling pathways. We also discuss the possibility of using RIPK2 as a new therapeutic target in IBD.

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Section: Recent Progress In Receptor-interacting Serine/ Threonine Kinase 2 Inhibitorsmentioning

confidence: 99%

RIPK2 as a New Therapeutic Target in Inflammatory Bowel Diseases

et al. 2021

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“…Having only a substituent in the 4-position, including Cl (17), t-Bu (18), OH (19) or OMe (20), was well tolerated for RIPK2 enzyme inhibition, but resulted in loss of selectivity, cell signaling inhibition or both. In order to better balance enzyme and cell signaling inhibition with selectivity versus ALK2, the R2 position on the central heterocycle was explored.…”

Section: Resultsmentioning

confidence: 99%

“…For a previous class of RIPK2 inhibitors (e.g. 12), we proposed that appropriate occupancy of the region between the gatekeeper and the C-helix was necessary to achieve NOD cell signaling inhibition, but not required for disruption of RIPK2 kinase activity [18,19].…”

Section: Resultsmentioning

confidence: 99%

“…The percent inhibition at a specified concentration was determined or IC50 values were calculated based on a dose range of inhibitor concentrations using non-linear regression in GraphPad Prism software. Compound 12 [18] and DMSO were used as a positive and negative controls, respectively.…”

Section: -(mentioning

confidence: 99%

“…(1) [9] , Gefitinib (2) [10], OD36 (3) and OD38 (4) [11], [12], Ponatinib (6) [13], GSK583 (7) [14], 8a and its pro-drug 8b [15], 9 and 10 [16], and 11 [17] (Figure 1). Recently, our laboratory identified another class of potent RIPK2/NOD signaling inhibitors based on a 3,5diaryl-2-aminopyridine scaffold, exemplified by CSLP37 (12) [18]. This latter class of compounds was shown to disrupt XIAP-RIPK2 interactions mitigating NOD2 inflammatory signaling [19].…”

Section: Introductionmentioning

confidence: 99%

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