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<p>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 I<sup>1/2</sup> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月8日

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  • Haixia Su,
  • Guofeng Chen,
  • Hang Xie,
  • Wanchen Li,
  • Muya Xiong,
  • Jian He,
  • Hangchen Hu,
  • Wenfeng Zhao,
  • Qiang Shao,
  • Minjun Li,
  • Qiang Zhao,
  • Yechun Xu

摘要

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.