2. Academic Validation
  3. Design, synthesis, and evaluation of potent RIPK1 inhibitors with in vivo anti-inflammatory activity

Design, synthesis, and evaluation of potent RIPK1 inhibitors with in vivo anti-inflammatory activity

  • Eur J Med Chem. 2022 Jan 15;228:114036. doi: 10.1016/j.ejmech.2021.114036.
Zhanhui Li 1,  Yongjin Hao 1,  Chengkui Yang 2,  Qing Yang 1,  Shuwei Wu 1,  Haikuo Ma 1,  Sheng Tian 1,  Haohao Lu 2,  Jingrui Wang 2,  Tao Yang 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 Key Laboratory of Synthetic Biology Regulatory Elements, Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medial College, Beijing, Suzhou Institute of Systems Medicine, Suzhou, 215123, Jiangsu, PR China.
  • 3 Key Laboratory of Synthetic Biology Regulatory Elements, Institute of Systems Medicine, 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: 34906762 DOI: 10.1016/j.ejmech.2021.114036
Abstract

RIPK1 plays a key role in the Necroptosis pathway that regulates inflammatory signaling and cell death in various diseases, including inflammatory and neurodegenerative diseases. Herein, we report a series of potent RIPK1 inhibitors, represented by compound 70. Compound 70 efficiently blocks Necroptosis induced by TNFα in both human and mouse cells (EC50 = 17-30 nM). Biophysical assay demonstrates that compound 70 potently binds to RIPK1 (Kd = 9.2 nM), but not RIPK3 (Kd > 10,000 nM). Importantly, compound 70 exhibits greatly improved metabolic stability in human and rat liver microsomes compared to compound 6 (PK68), a RIPK1 Inhibitor reported in our previous work. In addition, compound 70 displays high permeability in Caco-2 cells and excellent in vitro safety profiles in hERG and CYP assays. Moreover, pre-treatment of 70 significantly ameliorates hypothermia and lethal shock in SIRS mice model. Lastly, compound 70 possesses favorable pharmacokinetic parameters with moderate clearance and good oral bioavailability in SD rat. Taken together, our work supports 70 as a potent RIPK1 Inhibitor and highlights its potential as a prototypical lead for further development in necroptosis-associated inflammatory disorders.

Keywords

Inflammatory; Kinase inhibitor; Necroptosis; RIPK1.

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