2. Academic Validation
  3. HS-1371, a novel kinase inhibitor of RIP3-mediated necroptosis

HS-1371, a novel kinase inhibitor of RIP3-mediated necroptosis

  • Exp Mol Med. 2018 Sep 20;50(9):1-15. doi: 10.1038/s12276-018-0152-8.
Han-Hee Park  # 1 2,  Se-Yeon Park  # 1 2,  Shinmee Mah 3 4,  Jung-Hee Park 5,  Soon-Sun Hong 6,  Sungwoo Hong 7 8,  You-Sun Kim 9 10
Affiliations

Affiliations

  • 1 Department of Biochemistry, Ajou University School of Medicine, Suwon, Korea.
  • 2 Department of Biomedical Sciences, Graduate School, Suwon, Korea.
  • 3 Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon, 34141, Korea.
  • 4 Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Korea.
  • 5 Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, 22332, Korea.
  • 6 Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, 22332, Korea. [email protected].
  • 7 Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon, 34141, Korea. [email protected].
  • 8 Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Korea. [email protected].
  • 9 Department of Biochemistry, Ajou University School of Medicine, Suwon, Korea. [email protected].
  • 10 Department of Biomedical Sciences, Graduate School, Suwon, Korea. [email protected].
  • # Contributed equally.
PMID: 30237400 DOI: 10.1038/s12276-018-0152-8
Abstract

Necroptosis is a type of programmed cell death that usually occurs under apoptosis-deficient conditions. Receptor-interacting protein kinase-3 (RIP3, or RIPK3) is a central player in Necroptosis, and its kinase activity is essential for downstream necroptotic signaling events. Since RIP3 kinase activity has been associated with various diseases, the development of specific RIP3 inhibitors is an attractive strategy for therapeutic application. In this study, we identified a potent RIP3 inhibitor, HS-1371, by the extensive screening of chemical libraries focused on kinases. HS-1371 directly binds to RIP3 in an ATP-competitive and time-independent manner, providing a mechanism of action. Moreover, the compound inhibited TNF-induced Necroptosis but did not inhibit TNF-induced Apoptosis, indicating that this novel inhibitor has a specific inhibitory effect on RIP3-mediated Necroptosis via the suppression of RIP3 kinase activity. Our results suggest that HS-1371 could serve as a potential preventive or therapeutic agent for diseases involving RIP3 hyperactivation.

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