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

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

  • Biochem Pharmacol. 2023 Jun 12;115647. doi: 10.1016/j.bcp.2023.115647.
Yujun Lai 1,  Xinhui Wang 2,  Xue Sun 3,  Shuwei Wu 4,  Xin Chen 3,  Chengkui Yang 2,  Wei Zhang 2,  Xiaoliang Yu 2,  Yushan Tong 5,  Feng Ma 2,  Heng Zheng 6,  Xiaohu Zhang 7,  Sudan He 8
Affiliations

Affiliations

  • 1 School of Life Science and Technology, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China; Key Laboratory of Synthetic Biology Regulatory Elements, Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China; Suzhou Institute of Systems Medicine, Suzhou 215123, China.
  • 2 Key Laboratory of Synthetic Biology Regulatory Elements, Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China; Suzhou Institute of Systems Medicine, Suzhou 215123, China.
  • 3 The First Affiliated hospital of Soochow University, Suzhou, China.
  • 4 Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.
  • 5 Xi'an jiaotong-Liverpool University, Suzhou, China.
  • 6 School of Life Science and Technology, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China. Electronic address: zhengh18@hotmail.com.
  • 7 Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China. Electronic address: xiaohuzhang@suda.edu.cn.
  • 8 Key Laboratory of Synthetic Biology Regulatory Elements, Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China; Suzhou Institute of Systems Medicine, Suzhou 215123, China; State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China. Electronic address: hesd@ism.pumc.edu.cn.
PMID: 37315817 DOI: 10.1016/j.bcp.2023.115647
Abstract

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.

Keywords

IBD; Inflammatory diseases; NOD; RIPK2; RIPK2 inhibitor; Zharp2-1.

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