Frontiers in Cell and Developmental Biology (Dec 2020)
Discovery of a Potent RIPK3 Inhibitor for the Amelioration of Necroptosis-Associated Inflammatory Injury
- Kaijiang Xia,
- Fang Zhu,
- Fang Zhu,
- Fang Zhu,
- Fang Zhu,
- Chengkui Yang,
- Chengkui Yang,
- Chengkui Yang,
- Shuwei Wu,
- Yu Lin,
- Haikuo Ma,
- Xiaoliang Yu,
- Xiaoliang Yu,
- Xiaoliang Yu,
- Cong Zhao,
- Cong Zhao,
- Cong Zhao,
- Yuting Ji,
- Yuting Ji,
- Yuting Ji,
- Yuting Ji,
- Wenxiang Ge,
- Wenxiang Ge,
- Wenxiang Ge,
- Jingrui Wang,
- Jingrui Wang,
- Jingrui Wang,
- Yayun Du,
- Yayun Du,
- Yayun Du,
- Yayun Du,
- Wei Zhang,
- Wei Zhang,
- Wei Zhang,
- Tao Yang,
- Tao Yang,
- Tao Yang,
- Tao Yang,
- Xiaohu Zhang,
- Sudan He,
- Sudan He,
- Sudan He,
- Sudan He
Affiliations
- Kaijiang Xia
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, China
- Fang Zhu
- Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medial College, Beijing, China
- Fang Zhu
- Suzhou Institute of Systems Medicine, Suzhou, China
- Fang Zhu
- Key Laboratory of Synthetic Biology Regulatory Elements, Chinese Academy of Medical Sciences, Beijing, China
- Fang Zhu
- Cyrus Tang Hematology Center and Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, China
- Chengkui Yang
- Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medial College, Beijing, China
- Chengkui Yang
- Suzhou Institute of Systems Medicine, Suzhou, China
- Chengkui Yang
- Key Laboratory of Synthetic Biology Regulatory Elements, Chinese Academy of Medical Sciences, Beijing, China
- Shuwei Wu
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, China
- Yu Lin
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, China
- Haikuo Ma
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, China
- Xiaoliang Yu
- Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medial College, Beijing, China
- Xiaoliang Yu
- Suzhou Institute of Systems Medicine, Suzhou, China
- Xiaoliang Yu
- Key Laboratory of Synthetic Biology Regulatory Elements, Chinese Academy of Medical Sciences, Beijing, China
- Cong Zhao
- Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medial College, Beijing, China
- Cong Zhao
- Suzhou Institute of Systems Medicine, Suzhou, China
- Cong Zhao
- Key Laboratory of Synthetic Biology Regulatory Elements, Chinese Academy of Medical Sciences, Beijing, China
- Yuting Ji
- Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medial College, Beijing, China
- Yuting Ji
- Suzhou Institute of Systems Medicine, Suzhou, China
- Yuting Ji
- Key Laboratory of Synthetic Biology Regulatory Elements, Chinese Academy of Medical Sciences, Beijing, China
- Yuting Ji
- School of Life Sciences and Technology, China Pharmaceutical University, Nanjing, China
- Wenxiang Ge
- Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medial College, Beijing, China
- Wenxiang Ge
- Suzhou Institute of Systems Medicine, Suzhou, China
- Wenxiang Ge
- Key Laboratory of Synthetic Biology Regulatory Elements, Chinese Academy of Medical Sciences, Beijing, China
- Jingrui Wang
- Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medial College, Beijing, China
- Jingrui Wang
- Suzhou Institute of Systems Medicine, Suzhou, China
- Jingrui Wang
- Key Laboratory of Synthetic Biology Regulatory Elements, Chinese Academy of Medical Sciences, Beijing, China
- Yayun Du
- Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medial College, Beijing, China
- Yayun Du
- Suzhou Institute of Systems Medicine, Suzhou, China
- Yayun Du
- Key Laboratory of Synthetic Biology Regulatory Elements, Chinese Academy of Medical Sciences, Beijing, China
- Yayun Du
- Cyrus Tang Hematology Center and Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, China
- Wei Zhang
- Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medial College, Beijing, China
- Wei Zhang
- Suzhou Institute of Systems Medicine, Suzhou, China
- Wei Zhang
- Key Laboratory of Synthetic Biology Regulatory Elements, Chinese Academy of Medical Sciences, Beijing, China
- Tao Yang
- Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medial College, Beijing, China
- Tao Yang
- Suzhou Institute of Systems Medicine, Suzhou, China
- Tao Yang
- Key Laboratory of Synthetic Biology Regulatory Elements, Chinese Academy of Medical Sciences, Beijing, China
- Tao Yang
- Cyrus Tang Hematology Center and Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, China
- Xiaohu Zhang
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, China
- Sudan He
- Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medial College, Beijing, China
- Sudan He
- Suzhou Institute of Systems Medicine, Suzhou, China
- Sudan He
- Key Laboratory of Synthetic Biology Regulatory Elements, Chinese Academy of Medical Sciences, Beijing, China
- Sudan He
- Cyrus Tang Hematology Center and Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, China
- DOI
- https://doi.org/10.3389/fcell.2020.606119
- Journal volume & issue
-
Vol. 8
Abstract
Necroptosis is a form of regulated necrosis that requires the activation of receptor-interacting kinase 3 (RIPK3 or RIP3) and its phosphorylation of the substrate MLKL (mixed lineage kinase domain-like protein). Necroptosis has emerged as important cell death involved in the pathogenesis of various diseases including inflammatory diseases, degenerative diseases, and cancer. Here, we discovered a small molecule Zharp-99 as a potent inhibitor of necroptosis through blocking the kinase activity of RIPK3. Zharp-99 efficiently blocks necroptosis induced by ligands of the death receptor and Toll-like receptor as well as viral infection in human, rat and mouse cells. Zharp-99 strongly inhibits cellular activation of RIPK3, and MLKL upon necroptosis stimuli. Zharp-99 directly blocks the kinase activity of RIPK3 without affecting RIPK1 kinase activity at the tested concentration. Importantly, Zharp-99 exerts effective protection against TNF-α induced systemic inflammatory response syndrome in the mouse model. Zharp-99 displays favorable in vitro safety profiles and in vivo pharmacokinetic parameters. Thus, our study demonstrates Zharp-99 as a potent inhibitor of RIPK3 kinase and also highlights its potential for further development of new approaches for treating necroptosis-associated inflammatory disorders.
Keywords
