2. Academic Validation
  3. Ring closure strategy leads to potent RIPK3 inhibitors

Ring closure strategy leads to potent RIPK3 inhibitors

  • Eur J Med Chem. 2021 May 5:217:113327. doi: 10.1016/j.ejmech.2021.113327.
Shuwei Wu 1,  Chen Xu 1,  Kaijiang Xia 1,  Yu Lin 1,  Sheng Tian 1,  Haikuo Ma 1,  Yuting Ji 2,  Fang Zhu 2,  Sudan He 3,  Xiaohu Zhang 4
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, 215123, PR China.
  • 2 Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medial College, Beijing, Suzhou Institute of Systems Medicine, Suzhou, 215123, Jiangsu, PR China; Cyrus Tang Hematology Center, Jiangsu Institute of Hematology and Collaborative Innovation Center of Hematology, Soochow University, Suzhou, 215123, PR China.
  • 3 Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medial College, Beijing, Suzhou Institute of Systems Medicine, Suzhou, 215123, Jiangsu, PR China; Cyrus Tang Hematology Center, Jiangsu Institute of Hematology and Collaborative Innovation Center of Hematology, Soochow University, Suzhou, 215123, PR China. Electronic address: hesudan2018@163.com.
  • 4 Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, 215123, PR China. Electronic address: xiaohuzhang@suda.edu.cn.
PMID: 33730678 DOI: 10.1016/j.ejmech.2021.113327
Abstract

Necroptosis is a form of regulated necrotic cell death that is independent of caspases. Receptor-interacting protein kinase 3 (RIPK3) has been identified as a key regulator for Necroptosis, and has been proposed as a potential therapeutic target for the treatment of diseases associated with Necroptosis. In this report, we describe the design, synthesis, and evaluation of a series of novel RIPK3 inhibitors. The lead compound 38 exhibited potent activity (EC50 = 0.42 μM) in blocking TNFα, Smac mimetic and z-VAD (TSZ) induced cell death in HT-29 cells. Mechanistic studies showed that compound 38 bound to RIPK3 with high affinity (Kd = 7.1 nM), and inhibited RIPK3 kinase activity in a ADP-Glo functional assay. In addition, compound 38 displayed good selectivity over another Necroptosis regulator RIPK1 (Kd = 6000 nM). Furthermore, compound 38 demonstrated excellent in vitro safety profiles with minimal inhibition of CYP isozymes and hERG Potassium Channel. Lastly, compound 38 efficiently blocked hypothermia and death in mice in the TNFα-induced systemic inflammatory response syndrome model.

Keywords

Cell death; Inflammation; Kinase; Necroptosis; RIPK1; RIPK3.

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