Design, Synthesis, and Structure-Activity Relationship Study of Potent MAPK11 Inhibitors

Molecules. 2021 Dec 29;27(1):203. doi: 10.3390/molecules27010203.

Abstract

Huntington's disease (HD) is a rare single-gene neurodegenerative disease, which can only be treated symptomatically. Currently, there are no approved drugs for HD on the market. Studies have found that MAPK11 can serve as a potential therapeutic target for HD. Regrettably, no MAPK11 small molecule inhibitors have been approved at present. This paper presents three series of compounds that were designed and synthesized based on the structure of skepinone-L, a known MAPK14 inhibitor. Among the synthesized compounds, 13a and 13b, with IC50 values of 6.40 nM and 4.20 nM, respectively, displayed the best inhibitory activities against MAPK11. Furthermore, the structure-activity relationship (SAR) is discussed in detail, which is constructive in optimizing the MAPK11 inhibitors for better activity and effect against HD.

Keywords: Huntington’s disease; MAPK11; inhibitors; mHTT protein.

MeSH terms

  • Animals
  • Binding Sites
  • Chemistry Techniques, Synthetic
  • Drug Design*
  • Humans
  • Mitogen-Activated Protein Kinase 11 / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase 11 / chemistry*
  • Molecular Conformation
  • Molecular Docking Simulation*
  • Molecular Dynamics Simulation*
  • Molecular Structure
  • Protein Binding
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Protein Kinase Inhibitors
  • Mitogen-Activated Protein Kinase 11