Discovery of LT-1339-553 as a Potent RIPK1 Inhibitor for Schistosomiasis-Induced Hepatic Fibrosis

  • J Med Chem. 2026 May 28;69(10):12069-12098. doi: 10.1021/acs.jmedchem.5c03775.
Ju-Lu Lu  1 ,  Qin-Di He  2 ,  Yi-Han Yang  2 ,  Jing-Ping Li  1 ,  Si-Rui Mo  3 ,  Li Liang  2 ,  Ya-Qi Zhang  2 ,  Si-Ming Jia  2 ,  Zi-Tian Cheng  2 ,  Jie Cheng  2 ,  Pei Yang  2 ,  Hong-Mei Li  2 ,  Tao Lu  4 ,  Ya-Dong Chen  5 ,  Li-Jun Song  1 ,  Shuai Lu  2
Affiliations
  • 1. National Health Commission Key Laboratory of Parasitic Disease Control and Prevention, Jiangsu Provincial Key Laboratory on Parasite and Vector Control Technology, Jiangsu Provincial Medical Key Laboratory, Jiangsu Institute of Parasitic Diseases, Wuxi214064, P.R. China.
  • 2. School of Science, China Pharmaceutical University, Nanjing211198, P.R. China.
  • 3. School of Pharmacy, Youjiang Medical University for Nationalities, Baise533000, P.R. China.
  • 4. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing210009, P.R. China.
  • 5. Laboratory of Molecular Design and Drug Discovery, China Pharmaceutical University, Nanjing211198, P.R. China.
PMID: 42142075 DOI: 10.1021/acs.jmedchem.5c03775
Abstract

Hepatic fibrosis, a key pathological driver of chronic liver disease progression, lacks effective targeted therapies. Receptor-interacting protein kinase 1 (RIPK1) has emerged as a promising therapeutic target. Herein, we developed a highly potent and selective RIPK1 Inhibitor, LT-1339-553 (30), through structure-based optimization. Compound 30 exhibited potent RIPK1 inhibition (IC50 = 4.32 nM) and cellular antinecroptotic activity (EC50 = 14.43 nM). In a murine model of hepatic fibrosis, 30 significantly alleviated liver injury, inflammation, and Collagen deposition. Mechanistic studies revealed that its antifibrotic effects were associated with suppression of the Akt/PI3K/NF-κB and IL-17 pathways. Furthermore, 30 demonstrated good oral bioavailability and a favorable safety profile. These results position 30 as a promising candidate for the treatment of hepatic fibrosis.

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