Discovery of novel 5-phenylpyrazol receptor interacting protein 1(RIP1) kinase inhibitors as anti-necroptosis agents by combining virtual screening and in vitro and in vivo experimental evaluations

  • Bioorg Chem. 2024 Jan:142:106964. doi: 10.1016/j.bioorg.2023.106964.
Ying Shi  1 ,  Jiaqin Tang  2 ,  Shumeng Zhi  2 ,  Ruiqi Jiang  2 ,  Qing Huang  2 ,  Lei Sun  2 ,  Zhizhong Wang  3 ,  Yanran Wu  4
Affiliations
  • 1. Key Laboratory of Protection, Development and Utilization of Medicinal Resources in Liupanshan Area (Ningxia Medical University), Ministry of Education, School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan 750004, China. Electronic address: [email protected].
  • 2. Key Laboratory of Protection, Development and Utilization of Medicinal Resources in Liupanshan Area (Ningxia Medical University), Ministry of Education, School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan 750004, China.
  • 3. Key Laboratory of Protection, Development and Utilization of Medicinal Resources in Liupanshan Area (Ningxia Medical University), Ministry of Education, School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan 750004, China. Electronic address: [email protected].
  • 4. Key Laboratory of Protection, Development and Utilization of Medicinal Resources in Liupanshan Area (Ningxia Medical University), Ministry of Education, School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan 750004, China. Electronic address: [email protected].
PMID: 37976678 DOI: 10.1016/j.bioorg.2023.106964
Abstract

Necroptosis is one of the modes of cell death, and its occurrence and development are associated with the development of numerous diseases. To prevent the progression of Necroptosis, it is crucial to inhibit the phosphorylation of three proteins: receptor-interacting protein kinase 1 (RIP1), RIP3, and Mixed Lineage Kinase domain-like protein (MLKL). Through virtual and experimental screening approaches, we have identified 8 small molecular inhibitors with potent antinecroptotic activity and binding affinity to RIP1. Among these compounds, SY-1 demonstrated the most remarkable antinecroptotic activity (EC50 = 105.6 ± 9.6 nM) and binding affinity (RIP1 Kd = 49 nM). It effectively blocked Necroptosis and impeded the formation of necrosomes by inhibiting the phosphorylations of the RIP1/RIP3/MLKL pathway triggered by TSZ (TNFα, Smac mimetic and Z-VAD-fmk). Furthermore, SY-1 exhibited a protective effect against tumor necrosis factor (TNF)-induced hypothermia in mice and significantly improved the survival rate (100 %, 30 mg/kg) of mice with systemic inflammatory response syndrome (SIRS) in a dose-dependent manner. Pharmacokinetic parameters of SY-1 were also collected in vitro and in vivo. These results strongly suggest that SY-1 and its derivatives warrant further investigation for their potential therapeutic applications.

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