HS-1371, a Novel Kinase Inhibitor of RIP3-mediated Necroptosis

Overview

Journal Exp Mol Med

Specialties Biochemistry
Molecular Biology

Date 2018 Sep 22

PMID 30237400

Citations 25

Authors

Han-Hee Park

Se-Yeon Park

Shinmee Mah

Jung-Hee Park

Soon-Sun Hong

Sungwoo Hong

You-Sun Kim

Affiliations

Soon will be listed here.

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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