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.
|Number of pages||21|
|Journal||Journal of Medicinal Chemistry|
|State||Published - Apr 9 2020|
Bibliographical noteFunding Information:
We would like to thank the National Institutes of Health (R01 CA188354 to K.B.K. and R01 GM111084 to S.L.), National Research Foundation of Korea (2018R1D1A1A02086334 to A.B. and MRC2017R A5A2015541 to J.T.H.) for financially supporting this work.
© 2020 American Chemical Society.
ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery