2. Academic Validation
  3. Discovery of benzothiazole derivatives as novel orally receptor-interacting protein kinase 1 (RIPK1) inhibitors for inflammatory disease therapy

Discovery of benzothiazole derivatives as novel orally receptor-interacting protein kinase 1 (RIPK1) inhibitors for inflammatory disease therapy

  • Eur J Med Chem. 2026 Jan 15;302(Pt 3):118380. doi: 10.1016/j.ejmech.2025.118380.
Chufeng Zhang 1,  Yulian Chen 1,  Minghai Tang 1,  Shunjie Zhang 2,  Wei Yan 3,  Yong Li 4,  Na Li 1,  Haoyu Zhao 5,  Mingrui Li 1,  Ziyan Ma 1,  Taijin Wang 6,  Lijuan Chen 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Biotherapy, Cancer Center and Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu, 610041, China.
  • 2 Department of Emergency Medicine, Institute of Disaster Medicine, Institute of Emergency Medicine, Disaster Medical Center, West China Hospital of Sichuan University, Chengdu, 610041, China.
  • 3 Laboratory of Neuro-System and Multimorbidity, West China Hospital of Sichuan University, Chengdu, 610041, China.
  • 4 Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, West China Hospital of Sichuan University, Chengdu, 610041, China.
  • 5 School of Pharmacy/School of Modern Chinese Medicine Industry, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
  • 6 Chengdu Zenitar Biomedical Technology Co., Ltd., Chengdu, 610041, China. Electronic address: [email protected].
  • 7 State Key Laboratory of Biotherapy, Cancer Center and Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu, 610041, China; Chengdu Zenitar Biomedical Technology Co., Ltd., Chengdu, 610041, China. Electronic address: [email protected].
PMID: 41297387 DOI: 10.1016/j.ejmech.2025.118380
Abstract

Receptor-interacting protein kinase 1 (RIPK1), a significant node in the TNF signaling pathway, plays a critical role in modulating inflammatory cell proliferation, Apoptosis, and Necroptosis. Herein, we report the discovery of benzothiazole derivatives as potent RIPK1 inhibitors. Among them, compound 2q demonstrated significant anti-necroptotic activity by protecting cells against Necroptosis. In addition, compound 2q exhibited excellent bioavailability and provided strong protective effects in the systemic inflammatory response syndrome (SIRS) model and humanized acute graft versus host disease (GVHD) model. Collectively, these findings indicate that 2q is a novel and promising candidate for the treatment of inflammatory diseases.

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