2. Academic Validation
  3. Discovery of Potent and Balanced Dual RIPK2 and 3 Inhibitors as a New Strategy for the Treatment of Inflammatory Bowel Diseases

Discovery of Potent and Balanced Dual RIPK2 and 3 Inhibitors as a New Strategy for the Treatment of Inflammatory Bowel Diseases

  • J Med Chem. 2025 Apr 10;68(7):7539-7559. doi: 10.1021/acs.jmedchem.4c03226.
Duo Ma 1,  Shuang Hu 2,  Chun Wang 1,  Jiaxin Ai 1,  Jiahai Ma 1,  Tianwen Gao 1 3,  Yaling Hong 1,  Zhengxing Wu 1,  Mingzhen Gu 1,  XiaoXin Tang 1,  YanTai Chang 1,  QiHang Chen 1,  Shuo Chen 1,  Qing Yu 1,  JunJie Yang 1,  Chen Zhang 1,  Chong Li 1,  Xuesong Liu 1,  Jingbo Shi 1,  Xinhua Liu 1,  Yuhai Liu 1 4,  Mingming Liu 1
Affiliations

Affiliations

  • 1 Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, School of Pharmacy, Anhui Medical University, Hefei 230032, China.
  • 2 Department of Pharmacy, Eye & ENT Hospital of Fudan University, Shanghai 200031, China.
  • 3 Department of Pharmacy, Fuyang Hospital of Anhui Medical University, Fuyang 236112, China.
  • 4 Department of Gastrointestinal Surgery, The Third Affiliated Hospital of Anhui Medical University, The First People's Hospital of Hefei, Binhu Hospital District, Hefei 230041, China.
PMID: 40131099 DOI: 10.1021/acs.jmedchem.4c03226
Abstract

Receptor-interacting serine/threonine protein kinase 2 (RIPK2) and RIPK3 have been demonstrated to be promising targets for treating multiple inflammatory diseases, including inflammatory bowel diseases (IBDs). Due to the complexity of IBD pathogenesis, on the basis of synergy strategies, we herein describe the discovery and optimization of a series of N,7-diaryl-quinazolin-4-amine derivatives as dual RIPK2 and RIPK3 inhibitors. Based on a step-by-step process involving three rounds of structural modifications, compound 29 was identified as the most one, exhibiting balanced potency against RIPK2 (IC50 = 12 nM) and RIPK3 (IC50 = 18 nM), as well as demonstrating good selectivity over Other kinase targets. Further biological evaluation confirmed that compound 29 could bind directly to RIPK2 and RIPK3, effectively suppressing NOD-induced cytokine production and cellular Necroptosis. Notably, compound 29 displayed significant therapeutic effects in a DSS-induced colitis mouse model, with no detectable toxicity, indicating its promising therapeutic potential as RIPK2/RIPK3 dual inhibitors for treatment of IBD.

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