Structure-based design of potent and selective inhibitors targeting RIPK3 for eliminating on-target toxicity in vitro

Haixia Su (), Guofeng Chen, Hang Xie, Wanchen Li, Muya Xiong, Jian He, Hangchen Hu, Wenfeng Zhao, Qiang Shao, Minjun Li, Qiang Zhao () and Yechun Xu ()
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Haixia Su: University of Chinese Academy of Sciences
Guofeng Chen: University of Chinese Academy of Sciences
Hang Xie: Nanjing University of Chinese Medicine
Wanchen Li: University of Nottingham Ningbo China
Muya Xiong: University of Chinese Academy of Sciences
Jian He: University of Chinese Academy of Sciences
Hangchen Hu: University of Chinese Academy of Sciences
Wenfeng Zhao: University of Chinese Academy of Sciences
Qiang Shao: University of Chinese Academy of Sciences
Minjun Li: Chinese Academy of Sciences
Qiang Zhao: University of Chinese Academy of Sciences
Yechun Xu: University of Chinese Academy of Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract The essential role of RIPK3 in necroptosis makes its inhibition a promising therapeutic strategy. However, the development of RIPK3 inhibitors has been hampered by on-target apoptosis and limited kinase selectivity. Inspired by the R69H mutation, which prevents on-target apoptosis by disrupting RIPK3 dimerization, we design LK-series inhibitors that effectively inhibit RIPK3 in biochemical assays and block TNF-α-induced necroptosis in both mouse L929 and human HT29 cells without inducing apoptosis. The representative compound, LK01003, shows high selectivity across a panel of 379 kinases. Our structural studies reveal that LK compounds act as Type I1/2 inhibitors, engaging a unique hydrophobic site and stabilizing an inactive conformation of RIPK3. Moreover, several type II inhibitors are also revealed to maintain RIPK3 in the inactive conformation and do not induce on-target apoptosis. These findings suggest a promising strategy for rational design of safe and selective inhibitors by locking the inactive conformation of RIPK3.

Date: 2025
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DOI: 10.1038/s41467-025-59432-8

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