2. Academic Validation
  3. Structure-based design of potent and selective inhibitors targeting RIPK3 for eliminating on-target toxicity in vitro

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

  • Nat Commun. 2025 May 8;16(1):4288. doi: 10.1038/s41467-025-59432-8.
Haixia Su # 1 2,  Guofeng Chen # 3,  Hang Xie # 4,  Wanchen Li # 5,  Muya Xiong 3,  Jian He 6 7,  Hangchen Hu 6,  Wenfeng Zhao 6,  Qiang Shao 6 7,  Minjun Li 8,  Qiang Zhao 9 10 11,  Yechun Xu 12 13 14
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Shanghai, 201203, China. suhaixia1@simm.ac.cn.
  • 2 University of Chinese Academy of Sciences, Beijing, 100049, China. suhaixia1@simm.ac.cn.
  • 3 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China.
  • 4 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
  • 5 Nottingham Ningbo China Beacons of Excellence Research and Innovation Institute, University of Nottingham Ningbo China, Ningbo, 315100, China.
  • 6 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Shanghai, 201203, China.
  • 7 University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 8 Shanghai Synchrotron Radiation Facility, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai, 201204, China.
  • 9 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Shanghai, 201203, China. zhaoq@simm.ac.cn.
  • 10 University of Chinese Academy of Sciences, Beijing, 100049, China. zhaoq@simm.ac.cn.
  • 11 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China. zhaoq@simm.ac.cn.
  • 12 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Shanghai, 201203, China. ycxu@simm.ac.cn.
  • 13 University of Chinese Academy of Sciences, Beijing, 100049, China. ycxu@simm.ac.cn.
  • 14 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China. ycxu@simm.ac.cn.
  • # Contributed equally.
PMID: 40341069 DOI: 10.1038/s41467-025-59432-8
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.

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