LMP2 Inhibitors as a Potential Treatment for Alzheimer's Disease

Deepak Bhattarai, Min Jae Lee, Ahruem Baek, In Jun Yeo, Zachary Miller, Yu Mi Baek, Sukyeong Lee, Dong Eun Kim, Jin Tae Hong, Kyung Bo Kim

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

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.

Original languageEnglish
Pages (from-to)3763-3783
Number of pages21
JournalJournal of Medicinal Chemistry
Volume63
Issue number7
DOIs
StatePublished - Apr 9 2020

Bibliographical note

Publisher Copyright:
© 2020 American Chemical Society.

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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