Potent Benzothiazole-Triazole RIPK1/RIPK3 Dual-Targeting Inhibitors for the Treatment of Systemic Inflammatory Response Syndrome

  • J Med Chem. 2026 May 28;69(10):12449-12467. doi: 10.1021/acs.jmedchem.6c00339.
Shanshan Hu  1  2 ,  Wenyan Zhou  1  2 ,  Yue Xu  1  2 ,  Qingqing Qin  1 ,  Shuyu Wang  1  2 ,  Zhuo Qu  1 ,  Ruyun Liu  1  2 ,  Yaping An  3 ,  Xiangdong Bai  3 ,  Wan-Nian Zhang  1  2 ,  Jian-Qiang Yu  1 ,  Yue Liu  1 ,  Jing Li  4 ,  Junyu Wang  5 ,  Chunlin Zhuang  1  2
Affiliations
  • 1. School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan 750004, China.
  • 2. The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China.
  • 3. The First People's Hospital of Yinchuan, The Second Clinical Medical College, Ningxia Medical University, Yinchuan 750001, China.
  • 4. Department of Precision Medicine, Changhai Hospital, Second Military Medical University (Naval Medical University), Shanghai 200433, China.
  • 5. Department of Neurosurgery, The Second Affiliated Hospital of Naval Medical University, Shanghai Institute of Neurosurgery, Shanghai 200003, China.
PMID: 42096648 DOI: 10.1021/acs.jmedchem.6c00339
Abstract

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and RIPK3 play a central role in Necroptosis for systemic inflammatory response syndrome (SIRS). Single-target RIPK1 inhibitors have shown limited clinical progress, and no RIPK3 inhibitors have reached clinical trials, supporting the development of dual RIPK1/RIPK3 inhibitors. In this study, novel benzothiazole-triazole derivatives were designed by hybridizing benzothiazole inhibitor SZM-594 and RIPK1 Inhibitor GSK'772. Most compounds exhibited potent nanomolar antinecroptotic activity and low cytotoxicity. Selected compounds were confirmed to effectively inhibit RIPK1 (Kd < 10 nM) and RIPK3 (Kd = ∼50 nM) in the nanomolar range. Compounds 10, 38, and 43 alleviated TNF-α-induced SIRS in mice by restoring body temperature, improving survival, and reducing IL-1β/IL-6 levels in the serum and multiple organs. Mechanistically, they blocked RIPK1, RIPK3, and MLKL phosphorylation, specifically inhibiting Necroptosis rather than Apoptosis. This study provides novel lead compounds for RIPK1/RIPK3 dual-targeting intervention and promising candidates for necroptosis-related inflammatory diseases.

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