2. Academic Validation
  3. Discovery of a cooperative mode of inhibiting RIPK1 kinase

Discovery of a cooperative mode of inhibiting RIPK1 kinase

  • Cell Discov. 2021 Jun 1;7(1):41. doi: 10.1038/s41421-021-00278-x.
Huyan Meng  # 1 2,  Guowei Wu  # 1 2,  Xinsuo Zhao  # 1 2,  Anhui Wang  # 3,  Dekang Li 1 2,  Yilun Tong 1 2,  Taijie Jin 1 2,  Ye Cao 1 2,  Bing Shan 1,  Shichen Hu 2 4,  Ying Li 2 4,  Lifeng Pan 4,  Xiaoxu Tian 5,  Ping Wu 5,  Chao Peng 5,  Junying Yuan 1 6,  Guohui Li 7,  Li Tan 8,  Zhaoyin Wang 9,  Ying Li 10
Affiliations

Affiliations

  • 1 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
  • 2 University of Chinese Academy of Sciences, Beijing, China.
  • 3 Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, Liaoning, China.
  • 4 Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
  • 5 National Facility for Protein Science, Zhangjiang Lab, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai, China.
  • 6 Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
  • 7 Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, Liaoning, China. ghli@dicp.ac.cn.
  • 8 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China. tanli@sioc.ac.cn.
  • 9 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China. zywang@sioc.ac.cn.
  • 10 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China. liying@sioc.ac.cn.
  • # Contributed equally.
PMID: 34075030 DOI: 10.1038/s41421-021-00278-x
Abstract

RIPK1, a death domain-containing kinase, has been recognized as an important therapeutic target for inhibiting Apoptosis, Necroptosis, and inflammation under pathological conditions. RIPK1 kinase inhibitors have been advanced into clinical studies for the treatment of various human diseases. One of the current bottlenecks in developing RIPK1 inhibitors is to discover new approaches to inhibit this kinase as only limited chemotypes have been developed. Here we describe Necrostatin-34 (Nec-34), a small molecule that inhibits RIPK1 kinase with a mechanism distinct from known RIPK1 inhibitors such as Nec-1s. Mechanistic studies suggest that Nec-34 stabilizes RIPK1 kinase in an inactive conformation by occupying a distinct binding pocket in the kinase domain. Furthermore, we show that Nec-34 series of compounds can synergize with Nec-1s to inhibit RIPK1 in vitro and in vivo. Thus, Nec-34 defines a new strategy to target RIPK1 kinase and provides a potential option of combinatorial therapy for RIPK1-mediated diseases.

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