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

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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.
Publisher
NATURE PUBLISHING GROUP
Issue Date
2018-09
Language
English
Article Type
Article
Keywords

MIXED LINEAGE KINASE; DOMAIN-LIKE PROTEIN; ISCHEMIA-REPERFUSION INJURY; CELL-DEATH; PROGRAMMED NECROSIS; REGULATED NECROSIS; RIP3 EXPRESSION; TNF-ALPHA; MELANOMA; PHOSPHORYLATION

Citation

EXPERIMENTAL AND MOLECULAR MEDICINE, v.50

ISSN
1226-3613
DOI
10.1038/s12276-018-0152-8
URI
http://hdl.handle.net/10203/246155
Appears in Collection
CH-Journal Papers(저널논문)
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