Identification and Characterization of Novel Receptor-Interacting Serine/Threonine‐Protein Kinase 2 Inhibitors Using Structural Similarity Analysis

Salla, Mohamed; Aguayo‐Ortiz, Rodrigo; Danmaliki, Gaddafi I.; Zare, Alaa; Said, Ahmed A.; Moore, Jack; Pandya, Vrajesh; Manaloor, Robin; Fong, Sunny; Blankstein, Anna R.; Gibson, Spencer B.; Garcia, Laura Ramos; Meier, Pascal; Bhullar, Khushwant S.; Hubbard, Basil P.; Fiteh, Yahya; Vliagoftis, Harissios; Goping, Ing Swie; Brocks, Dion R.; Hwang, Peter M.; Velázquez-Martínez, Carlos A.; Baksh, Shairaz

doi:10.1124/jpet.117.247163

Cited by 25 publications

(20 citation statements)

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“…We hypothesized that abnormalities in signaling proteins upstream from NF-κB, such as in RIPK2 may exist. Analysis of RIPK2 activation in IBC cell lines and patient tumor tissues revealed elevated kinase activity as determined by the surrogate detection tool, the use of a RIPK2 phospho antibody phosphorylated at Serine-176 (S176 indicative of active RIPK2) [ 27 , 49 ] and tyrosine-474 recognizing the autophosphorylation sites of RIPK2 (also indicative of active RIPK2) [ 50 ]. IBC cells lines show robust active RIPK2 when compared to non-IBC cell lines ( Figure 2 a).…”

Section: Resultsmentioning

confidence: 99%

RIPK2: New Elements in Modulating Inflammatory Breast Cancer Pathogenesis

Zare

Petrova

Agoumi

et al. 2018

Cancers

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Inflammatory breast cancer (IBC) is a rare and aggressive form of breast cancer that is associated with significantly high mortality. In spite of advances in IBC diagnoses, the prognosis is still poor compared to non-IBC. Due to the aggressive nature of the disease, we hypothesize that elevated levels of inflammatory mediators may drive tumorigenesis and metastasis in IBC patients. Utilizing IBC cell models and patient tumor samples, we can detect elevated NF-κB activity and hyperactivation of non-canonical drivers of NF-κB (nuclear factor kappaB)-directed inflammation such as tyrosine phosphorylated receptor-interacting protein kinase 2 (pY RIPK2), when compared to non-IBC cells or patients. Interestingly, elevated RIPK2 activity levels were present in a majority of pre-chemotherapy samples from IBC patients at the time of diagnosis to suggest that patients at diagnosis had molecular activation of NF-κB via RIPK2, a phenomenon we define as “molecular inflammation”. Surprisingly, chemotherapy did cause a significant increase in RIPK2 activity and thus molecular inflammation suggesting that chemotherapy does not resolve the molecular activation of NF-κB via RIPK2. This would impact on the metastatic potential of IBC cells. Indeed, we can demonstrate that RIPK2 activity correlated with advanced tumor, metastasis, and group stage as well as body mass index (BMI) to indicate that RIPK2 might be a useful prognostic marker for IBC and advanced stage breast cancer.

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Section: Resultsmentioning

confidence: 99%

RIPK2: New Elements in Modulating Inflammatory Breast Cancer Pathogenesis

Zare

Petrova

Agoumi

et al. 2018

Cancers

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“…WEHI-345, which was identified as a RIPK2 inhibitor by screening a proprietary library of 120 kinase inhibitors, delayed NF-κB activation by inhibiting polyubiquitination of RIPK2 and ameliorated experimental autoimmune encephalomyelitis (Nachbur et al, 2015). Salla et al (2018) identified and characterized two novel RIPK2 inhibitors by using molecular modeling and chemoinformatics analysis (Salla et al, 2018). The degree of suppression in DSSinduced colitis was significantly greater in mice treated with these RIPK2 inhibitors than in those treated with gefitinib (Salla et al, 2018).…”

Section: Nod2-ripk2 and Tlrs-ripk2 Axes In Inflammatory Bowel Diseasementioning

confidence: 99%

“…Salla et al (2018) identified and characterized two novel RIPK2 inhibitors by using molecular modeling and chemoinformatics analysis (Salla et al, 2018). The degree of suppression in DSSinduced colitis was significantly greater in mice treated with these RIPK2 inhibitors than in those treated with gefitinib (Salla et al, 2018). Although these studies utilizing RIPK2 inhibitors have not clearly shown whether such small molecules suppressed the activity of the NOD2-RIPK2 and TLRs-RIPK2 pathways to improve inflammation, their therapeutic and preventive effects seen in experimental IBD allow considering RIPK2 as a new therapeutic target in human IBD.…”

Section: Nod2-ripk2 and Tlrs-ripk2 Axes In Inflammatory Bowel Diseasementioning

confidence: 99%

“…Several RIPK2 inhibitors have been used for the treatment of experimental colitis. 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).…”

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

confidence: 99%

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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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“…This work is the first to demonstrate the efficacy and modulatory activity of a RIP2 targeting compound using a clinically relevant model of allergic asthma. Numerous inhibitors have both been discovered and developed for modulation of RIP2 activity (23,(35)(36)(37)(38)(39)(40)(41)(42)(43). The RIP2 inhibitor utilized in this study, GSK583, has been reported to be highly selective and exhibits strong potency even in vivo (23,39).…”

Section: Discussionmentioning

confidence: 99%

Immune Modulation of Allergic Asthma by Early Pharmacological Inhibition of RIP2

Miller

Shehat

Tigno-Aranjuez

2020

Preprint

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AbstractExposure to house dust mite (HDM) is highly associated with the development of allergic asthma. The adaptive immune response to HDM is largely T helper cell type 2 (Th2) dominant and a number of innate immune receptors have been identified which recognize HDM to initiate a Th2 response. Nucleotide-binding Oligomerization Domain-containing Protein 2 (NOD2) is a cytosolic sensor of peptidoglycan which is important for Th2 polarization. NOD2 mediates its signaling through its downstream effector kinase, Receptor-interacting Serine/Threonine Protein Kinase 2 (RIP2). We have previously shown that RIP2 is important in promoting HDM-associated allergic airway inflammation and Th2 immunity. In particular, we demonstrated that the effects of RIP2 were important early in the HDM response, likely within airway epithelial cells. However, the consequences of inhibiting RIP2 during this critical period has not yet been examined. In this study, we pharmacologically inhibited RIP2 activity during the initial exposure to allergen in an acute HDM model of asthma and determined the effect on the subsequent development of allergic airway disease. We show that early inhibition of RIP2 was sufficient to reduce lung histopathology and local airway inflammation while skewing the immune response from Th2 towards Th1. Using a chronic HDM asthma model, we demonstrate that inhibition of RIP2, despite attenuating airway inflammation and airway remodeling, was insufficient to reduce airway hyperresponsiveness. These data demonstrate the potential of pharmacological targeting of this kinase in asthma and support further development and optimization of RIP2 targeted therapies.

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Identification and Characterization of Novel Receptor-Interacting Serine/Threonine‐Protein Kinase 2 Inhibitors Using Structural Similarity Analysis

Cited by 25 publications

References 50 publications

RIPK2: New Elements in Modulating Inflammatory Breast Cancer Pathogenesis

RIPK2: New Elements in Modulating Inflammatory Breast Cancer Pathogenesis

RIPK2 as a New Therapeutic Target in Inflammatory Bowel Diseases

Immune Modulation of Allergic Asthma by Early Pharmacological Inhibition of RIP2

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