2. Academic Validation
  3. Potent and Selective RIPK1 Inhibitors Targeting Dual-Pockets for the Treatment of Systemic Inflammatory Response Syndrome and Sepsis

Potent and Selective RIPK1 Inhibitors Targeting Dual-Pockets for the Treatment of Systemic Inflammatory Response Syndrome and Sepsis

  • Angew Chem Int Ed Engl. 2022 Jan 26;61(5):e202114922. doi: 10.1002/anie.202114922.
Xiangbo Yang 1 2,  Huimin Lu 3 2,  Hang Xie 4 5,  Binbin Zhang 2 6,  Tianqing Nie 4 5,  Chen Fan 3,  Tao Yang 3 2,  Yechun Xu 4 2 6 5,  Haixia Su 4 2,  Wei Tang 3 2,  Bing Zhou 1 2 6
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 2 University of Chinese Academy of Sciences, Beijing, 10049, China.
  • 3 Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 4 Drug Discovery and Design Center, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 5 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
  • 6 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China.
PMID: 34851543 DOI: 10.1002/anie.202114922
Abstract

Sepsis, characterized with high risk of life-threatening organ dysfunction, represents a major cause of health loss and the World Health Organization (WHO) labelled sepsis as the most urgent unmet medical need in 2017. The emerging biological understanding of the role of RIPK1 in sepsis has opened up an exciting opportunity to explore potent and selective RIPK1 inhibitors as an effective therapeutic strategy for SIRS and sepsis therapy. Herein, we have synthesized a class of highly potent dual-mode RIPK1 inhibitors occupying both the allosteric and the ATP binding pockets, exemplified by compound 21 (ZB-R-55) which is about 10-fold more potent than GSK2982772, and exhibits excellent kinase selectivity, good oral pharmacokinetics and good therapeutic effects in the LPS-induced sepsis model, suggesting that compound ZB-R-55 is a highly promising preclinical candidate.

Keywords

Binding studies; Drug discovery; Necroptosis; RIPK1 inhibitors; Sepsis.

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