Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 63, Issue 7, Pages 3763-3783Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.0c00416
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Funding
- National Institutes of Health [R01 CA188354, R01 GM111084]
- National Research Foundation of Korea [2018R1D1A1A02086334, MRC2017R A5A2015541]
- National Research Foundation of Korea [2018R1D1A1A02086334] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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 beta 1, 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-1 alpha 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.
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