Discovery of a novel RIPK2 inhibitor for the treatment of inflammatory bowel disease

by Selleckchem | Oct 03 2023

Nucleotide-binding oligomerization domain-containing protein 1 and 2 (NOD 1/2) are important cytosolic pattern recognition receptors that initiate host immune response. The dysregulation of NOD signaling is highly associated with inflammatory bowel disease (IBD) that needs novel treatment options. Receptor-interacting protein kinase 2 (RIPK2) is a critical mediator of NOD signaling and considered a promising therapeutic target for IBD treatment. However, there are currently no RIPK2 inhibitors available for clinical use. Here, we report the discovery and characterization of Zharp2-1 as a novel and potent RIPK2 inhibitor that effectively blocks RIPK2 kinase function and NOD-mediated NF-κB/MAPK activation in both human and mouse cell lines. Zharp2-1 exhibits significantly superior solubility compared to the non-prodrug form of the advanced RIPK2 inhibitor prodrug GSK2983559. The improved solubility combined with favorable in vitro metabolic stability translated to excellent in vivo pharmacokinetic profiles for Zharp2-1. In addition, Zharp2-1 demonstrates better effects than GSK2983559 in inhibiting the muramyl dipeptide (MDP)-induced production of pro-inflammatory cytokines in human peripheral blood mononuclear cells (PBMCs) and MDP-induced peritonitis in mice. Furthermore, Zharp2-1 markedly reduces Listeria monocytogenes infection-induced cytokines release in both human and mouse cells. Importantly, Zharp2-1 significantly ameliorates DNBS-induced colitis in rats and suppressed pro-inflammatory cytokine release in intestinal specimens from IBD patients. Collectively, our findings indicate that Zharp2-1 is a promising RIPK2 inhibitor with the potential to be further developed for IBD therapy.

Comments:

That's an interesting report! It seems that the researchers have discovered and characterized a novel RIPK2 inhibitor called Zharp2-1, which shows promise as a therapeutic option for inflammatory bowel disease (IBD). Nucleotide-binding oligomerization domain-containing protein 1 and 2 (NOD 1/2) are important receptors involved in the initiation of the immune response, and dysregulation of NOD signaling is associated with IBD.

RIPK2, a critical mediator of NOD signaling, is considered a potential target for IBD treatment. However, there are currently no RIPK2 inhibitors available for clinical use. In this study, Zharp2-1 was found to effectively block RIPK2 kinase function and inhibit NOD-mediated NF-κB/MAPK activation in human and mouse cell lines.

Zharp2-1 demonstrated improved solubility compared to another RIPK2 inhibitor called GSK2983559. This improved solubility, along with favorable in vitro metabolic stability, translated to excellent pharmacokinetic profiles in animal models. Zharp2-1 showed better effects than GSK2983559 in inhibiting the production of pro-inflammatory cytokines in human peripheral blood mononuclear cells (PBMCs) and in a mouse model of peritonitis induced by muramyl dipeptide (MDP).

The researchers also observed that Zharp2-1 significantly reduced the release of cytokines induced by Listeria monocytogenes infection in both human and mouse cells. In an animal model of DNBS-induced colitis in rats, Zharp2-1 demonstrated a marked amelioration of colitis symptoms. Additionally, it suppressed the release of pro-inflammatory cytokines in intestinal specimens obtained from IBD patients.

Based on these findings, the researchers suggest that Zharp2-1 holds promise as a RIPK2 inhibitor for the treatment of IBD. Further development and research are warranted to explore its potential as a therapeutic option for IBD therapy.

It's important to note that as an AI language model, I can only provide information based on what is available up until my last knowledge update in September 2021. Therefore, I might not have the most recent updates on the development of Zharp2-1 or any other recent developments in the field of IBD therapy.