2. Academic Validation
  3. Discovery of potent necroptosis inhibitors targeting RIPK1 kinase activity for the treatment of inflammatory disorder and cancer metastasis

Discovery of potent necroptosis inhibitors targeting RIPK1 kinase activity for the treatment of inflammatory disorder and cancer metastasis

  • Cell Death Dis. 2019 Jun 24;10(7):493. doi: 10.1038/s41419-019-1735-6.
Jue Hou 1 2,  Jie Ju 1 2,  Zili Zhang 1 2,  Cong Zhao 1 2,  Zhanhui Li 3,  Jiyue Zheng 3,  Tian Sheng 3,  Hongjian Zhang 3,  Linkun Hu 4,  Xiaoliang Yu 1 2 5 6,  Wei Zhang 1 2 5 6,  Yangxin Li 7,  Meng Wu 1 2,  Haikuo Ma 8 9,  Xiaohu Zhang 10,  Sudan He 11 12 13 14
Affiliations

Affiliations

  • 1 Cyrus Tang Hematology Center and Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Soochow University, 215123, Suzhou, Jiangsu, China.
  • 2 Key Laboratory of Stem Cells and Biomedical Materials of Jiangsu Province and Chinese Ministry of Science and Technology, Soochow University, 215123, Suzhou, Jiangsu, China.
  • 3 Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, 215123, Suzhou, Jiangsu, China.
  • 4 Department of Urology, The First Affiliated Hospital of Soochow University, 188 Shizi Rd, 215006, Suzhou, Jiangsu, China.
  • 5 Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medial College, Beijing, 100005, China.
  • 6 Suzhou Institute of Systems Medicine, 215123, Suzhou, Jiangsu, China.
  • 7 Institute for Cardiovascular Science and Department of Cardiovascular Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
  • 8 Cyrus Tang Hematology Center and Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Soochow University, 215123, Suzhou, Jiangsu, China. [email protected].
  • 9 Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, 215123, Suzhou, Jiangsu, China. [email protected].
  • 10 Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, 215123, Suzhou, Jiangsu, China. [email protected].
  • 11 Cyrus Tang Hematology Center and Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Soochow University, 215123, Suzhou, Jiangsu, China. [email protected].
  • 12 Key Laboratory of Stem Cells and Biomedical Materials of Jiangsu Province and Chinese Ministry of Science and Technology, Soochow University, 215123, Suzhou, Jiangsu, China. [email protected].
  • 13 Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medial College, Beijing, 100005, China. [email protected].
  • 14 Suzhou Institute of Systems Medicine, 215123, Suzhou, Jiangsu, China. [email protected].
PMID: 31235688 DOI: 10.1038/s41419-019-1735-6
Abstract

Necroptosis is a form of regulated necrosis controlled by receptor-interacting kinase 1 (RIPK1 or RIP1), RIPK3 (RIP3), and pseudokinase Mixed Lineage Kinase domain-like protein (MLKL). Increasing evidence suggests that Necroptosis is closely associated with pathologies including inflammatory diseases, neurodegenerative diseases, and Cancer metastasis. Herein, we discovered the small-molecule PK6 and its derivatives as a novel class of Necroptosis inhibitors that directly block the kinase activity of RIPK1. Optimization of PK6 led to PK68, which has improved efficacy for the inhibition of RIPK1-dependent Necroptosis, with an EC50 of around 14-22 nM in human and mouse cells. PK68 efficiently blocks cellular activation of RIPK1, RIPK3, and MLKL upon Necroptosis stimuli. PK68 displays reasonable selectivity for inhibition of RIPK1 kinase activity and favorable pharmacokinetic properties. Importantly, PK68 provides strong protection against TNF-α-induced systemic inflammatory response syndrome in vivo. Moreover, pre-treatment of PK68 significantly represses metastasis of both melanoma cells and lung carcinoma cells in mice. Together, our study demonstrates that PK68 is a potent and selective inhibitor of RIPK1 and also highlights its great potential for use in the treatment of inflammatory disorders and Cancer metastasis.

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