Structure-based design of potent and selective inhibitors targeting RIPK3 for eliminating on-target toxicity in vitro
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 disrup...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-59432-8 |
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| author | Haixia Su Guofeng Chen Hang Xie Wanchen Li Muya Xiong Jian He Hangchen Hu Wenfeng Zhao Qiang Shao Minjun Li Qiang Zhao Yechun Xu |
| author_facet | Haixia Su Guofeng Chen Hang Xie Wanchen Li Muya Xiong Jian He Hangchen Hu Wenfeng Zhao Qiang Shao Minjun Li Qiang Zhao Yechun Xu |
| author_sort | Haixia Su |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-e9943619ebc54d9eaaff65ea63914525 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-e9943619ebc54d9eaaff65ea639145252025-08-20T01:49:39ZengNature PortfolioNature Communications2041-17232025-05-0116111510.1038/s41467-025-59432-8Structure-based design of potent and selective inhibitors targeting RIPK3 for eliminating on-target toxicity in vitroHaixia Su0Guofeng Chen1Hang Xie2Wanchen Li3Muya Xiong4Jian He5Hangchen Hu6Wenfeng Zhao7Qiang Shao8Minjun Li9Qiang Zhao10Yechun Xu11State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of SciencesSchool of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of SciencesSchool of Chinese Materia Medica, Nanjing University of Chinese MedicineNottingham Ningbo China Beacons of Excellence Research and Innovation Institute, University of Nottingham Ningbo ChinaSchool of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of SciencesState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of SciencesState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of SciencesState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of SciencesState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of SciencesShanghai Synchrotron Radiation Facility, Shanghai Advanced Research Institute, Chinese Academy of SciencesState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of SciencesState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of SciencesAbstract 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.https://doi.org/10.1038/s41467-025-59432-8 |
| spellingShingle | Haixia Su Guofeng Chen Hang Xie Wanchen Li Muya Xiong Jian He Hangchen Hu Wenfeng Zhao Qiang Shao Minjun Li Qiang Zhao Yechun Xu Structure-based design of potent and selective inhibitors targeting RIPK3 for eliminating on-target toxicity in vitro Nature Communications |
| title | Structure-based design of potent and selective inhibitors targeting RIPK3 for eliminating on-target toxicity in vitro |
| title_full | Structure-based design of potent and selective inhibitors targeting RIPK3 for eliminating on-target toxicity in vitro |
| title_fullStr | Structure-based design of potent and selective inhibitors targeting RIPK3 for eliminating on-target toxicity in vitro |
| title_full_unstemmed | Structure-based design of potent and selective inhibitors targeting RIPK3 for eliminating on-target toxicity in vitro |
| title_short | Structure-based design of potent and selective inhibitors targeting RIPK3 for eliminating on-target toxicity in vitro |
| title_sort | structure based design of potent and selective inhibitors targeting ripk3 for eliminating on target toxicity in vitro |
| url | https://doi.org/10.1038/s41467-025-59432-8 |
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