Design, synthesis and biological evaluation of triaryl compounds as novel 20S proteasome inhibitors

Bioorg Med Chem Lett. 2020 Nov 1;30(21):127508. doi: 10.1016/j.bmcl.2020.127508. Epub 2020 Aug 24.

Abstract

Thirty novel triaryl compounds were designed and synthesized based on the known proteasome inhibitor PI-1840. Most of them showed significant inhibition against the β5c subunit of human 20S proteasome, and five of them exhibited IC50 values at the sub-micromolar level, which were comparable to or even more potent than PI-1840. The most active two (1c and 1d) showed IC50 values of 0.12 and 0.18 μM against the β5c subunit, respectively, while they displayed no obvious inhibition against the β2c, β1c and β5i subunits. Molecular docking provided informative clues for the subunit selectivity. The potent and subunit selective proteasome inhibitors identified herein represent new chemical templates for further molecular optimization.

Keywords: Non-covalent; Proteasome inhibitors; Triaryl compounds.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / chemistry
  • Amides / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Oxadiazoles / chemistry
  • Oxadiazoles / pharmacology*
  • Proteasome Endopeptidase Complex / metabolism*
  • Proteasome Inhibitors / chemical synthesis
  • Proteasome Inhibitors / chemistry
  • Proteasome Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Amides
  • Oxadiazoles
  • Proteasome Inhibitors
  • Proteasome Endopeptidase Complex