Structure-based optimizations of a necroptosis inhibitor (SZM594) as novel protective agents of acute lung injury

https://doi.org/10.1016/j.cclet.2021.09.059Get rights and content

ABSTRACT

Targeting RIPK1 is a promising strategy for the treatment or alleviation of acute lung injury (ALI). SZM594, a benzothiazole compound previously developed by our research group, possessed good dual-targeting receptor-interacting protein kinase 1 (RIPK1) and RIPK3 activity and anti-necroptosis activity as well as acceptable in vivo efficacy. In this study, the cyclopropyl moiety of SZM594 was modified based on a structure-based design strategy. The resulting cyclohexanone-containing analogue 41 improved the selectivity toward RIPK1 over RIPK3 and the anti-necroptosis activity was also increased compared with those of SZM594. More importantly, compound 41 could inhibit the tumor necrosis factor-α (TNF-α) expression in lipopolysaccharide (LPS)-induced peritoneal macrophage cell model, and significantly alleviate LPS-induced ALI in a mouse model. This compound could significantly inhibit the expressions of the phosphorylation of RIPK1 and down-stream RIPK3 and mixed lineage kinase domain-like protein (MLKL). Thus, these cyclohexanone-containing benzothiazole analogues represent promising lead structures for the discovery of novel protective agents of ALI.

Graphical abstract

A series of derivatives of SZM594 were synthesized based on a structure-based design strategy. The cyclohexanone-containing analogue 41 improved the selectivity toward receptor-interacting protein kinase 1 (RIPK1) over RIPK3 and increased the anti-necroptosis activity and significantly alleviate lipopolysaccharide (LPS)-induced acute lung injury (ALI) in a mouse model.

Image, graphical abstract
  1. Download : Download high-res image (110KB)
  2. Download : Download full-size image

Section snippets

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

This work was funded by grants from the National Natural Science Foundation of China (Nos. 82022065, 81872791, 82073696, 81872880 and U20A20136); the Key Research and Development Program of Ningxia (No. 2019BFG02017, China); the Scientific and Technological Innovation Project of Science and Technology Commission of Shanghai Municipality (No. 21S11900800, China).

References (37)

  • A.P. Wheeler et al.

    Lancet

    (2007)
  • T.L. Petty et al.

    Chest

    (1971)
  • L. Su et al.

    Biomed. Pharmacother.

    (2020)
  • C. Huang et al.

    Lancet

    (2020)
  • D.H. Ingbar

    Clin. Chest Med.

    (2000)
  • W. Wu et al.

    Cell Rep.

    (2020)
  • Y. Wu et al.

    Acta Pharm. Sin. B

    (2020)
  • X. Qin et al.

    Biochim. Biophys. Acta Rev. Cancer

    (2019)
  • X. Teng et al.

    Bioorg. Med. Chem. Lett.

    (2005)
  • Y.S. Cho et al.

    Cell

    (2009)
  • F.C. Lin et al.

    Antioxidants (Basel)

    (2021)
  • H.K. Eltzschig et al.

    Nat. Rev. Drug Discov.

    (2014)
  • G.R. Budinger

    N.S. Chandel, Intens. Care Med.

    (2001)
  • M. Sauler et al.

    Annu. Rev. Physiol.

    (2019)
  • P. Tao et al.

    Nature

    (2020)
  • L. Mifflin et al.

    Nat. Rev. Drug. Discov.

    (2020)
  • R.K.S. Malireddi et al.

    J. Exp. Med.

    (2020)
  • A. Degterev et al.

    Nat. Chem. Biol.

    (2005)
  • Cited by (20)

    • Profiling of the chemical space on the phenyl group of substituted benzothiazole RIPK3 inhibitors

      2023, Bioorganic Chemistry
      Citation Excerpt :

      In order to further explain the effect of the substitutions, the molecular docking study of XY-1–127 was conducted. Based on our previous studies [14,24–26,32,33], the benzothiazole compound XY-1–127 was proposed as a type II inhibitor of RIP kinase. Thus, a “DFG-out” area containing crystal structure template was required in the docking study.

    View all citing articles on Scopus
    1

    These authors contributed equally to this work.

    View full text