LMP2 Inhibitors as a Potential Treatment for Alzheimer's Disease

J Med Chem. 2020 Apr 9;63(7):3763-3783. doi: 10.1021/acs.jmedchem.0c00416. Epub 2020 Mar 30.

Abstract

The immunoproteasome (iP), an inducible proteasome variant harboring three immunosubunits, low molecular mass polypeptide-2 (LMP2), multicatalytic endopeptidase complex subunit-1, and low molecular mass polypeptide-7 (LMP7), is involved in multiple facets of inflammatory responses. We recently reported that YU102, a dual inhibitor of the iP subunit LMP2 and the constitutive proteasome catalytic subunit β1, ameliorates cognitive impairments in mouse models of Alzheimer's disease (AD) independently of amyloid deposits. To investigate whether inhibition of LMP2 is sufficient to improve the cognitive functions of AD mice, here we prepared 37 YU102 analogues and identified a potent LMP2 inhibitor DB-310 (28) (IC50: 80.6 nM) with improved selectivity and permeability in cells overexpressing ABCB1 transporters. We show that DB-310 induces suppression of IL-1α production in microglia cells and improves cognitive functions in the Tg2576 transgenic mouse model of AD. This study supports that inhibition of LMP2 is a promising therapeutic strategy for treatment of AD.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Animals
  • Cell Line, Transformed
  • Cysteine Endopeptidases / metabolism*
  • Cysteine Proteinase Inhibitors / chemical synthesis
  • Cysteine Proteinase Inhibitors / therapeutic use*
  • Cysteine Proteinase Inhibitors / toxicity
  • Epithelial-Mesenchymal Transition / drug effects
  • Humans
  • Interleukin-1alpha / metabolism
  • Mice, Transgenic
  • Microglia / drug effects
  • Molecular Structure
  • Nootropic Agents / chemical synthesis
  • Nootropic Agents / therapeutic use*
  • Nootropic Agents / toxicity
  • Oligopeptides / chemical synthesis
  • Oligopeptides / therapeutic use*
  • Oligopeptides / toxicity
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / therapeutic use
  • Small Molecule Libraries / toxicity
  • Structure-Activity Relationship

Substances

  • Cysteine Proteinase Inhibitors
  • Il1a protein, mouse
  • Interleukin-1alpha
  • Nootropic Agents
  • Oligopeptides
  • Small Molecule Libraries
  • LMP-2 protein
  • Cysteine Endopeptidases