1. Academic Validation
  2. 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.
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.

Figures
Products