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

Experimental & Molecular Medicine
Han-Hee ParkYou-Sun Kim

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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Citations

Aug 17, 2019·American Journal of Physiology. Heart and Circulatory Physiology·Paras K MishraTakashi Matsui
Sep 12, 2019·Cellular Microbiology·David PajueloMichael Niederweis
Jul 3, 2020·Frontiers in Cell and Developmental Biology·Ying ShiCarol Pollock
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Dec 29, 2020·Frontiers in Cell and Developmental Biology·Kaijiang XiaSudan He
Apr 14, 2021·Future Medicinal Chemistry·Zhennan FangYiliang Li
Nov 23, 2019·Cellular and Molecular Gastroenterology and Hepatology·Adam D WertsDavid J Hackam
Oct 18, 2019·Journal of Medicinal Chemistry·Chunlin Zhuang, Fener Chen

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Methods Mentioned

BETA
column chromatography
X-ray
filter binding
Assay
transfection
reverse transcription-PCR
PCR
FACS
flow cytometry
fluorescence microscopy

Software Mentioned

PRISM
GraphPad Prism
GraFit
GraphPad
Discovery Studio
CDOCKER
Discovery
Studio

Related Concepts

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Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis