PMID- 32189500
OWN - NLM
STAT- MEDLINE
DCOM- 20201007
LR  - 20201007
IS  - 1520-4804 (Electronic)
IS  - 0022-2623 (Linking)
VI  - 63
IP  - 7
DP  - 2020 Apr 9
TI  - LMP2 Inhibitors as a Potential Treatment for Alzheimer's Disease.
PG  - 3763-3783
LID - 10.1021/acs.jmedchem.0c00416 [doi]
AB  - 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 beta1, 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) (IC(50): 80.6 nM) with improved selectivity and permeability in cells 
      overexpressing ABCB1 transporters. We show that DB-310 induces suppression of 
      IL-1alpha 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.
FAU - Bhattarai, Deepak
AU  - Bhattarai D
AD  - Department of Pharmaceutical Sciences, University of Kentucky, 789 South 
      Limestone, Lexington, Kentucky 40536-0596, United States.
FAU - Lee, Min Jae
AU  - Lee MJ
AD  - Department of Pharmaceutical Sciences, University of Kentucky, 789 South 
      Limestone, Lexington, Kentucky 40536-0596, United States.
FAU - Baek, Ahruem
AU  - Baek A
AD  - Department of Bioscience and Biotechnology, Konkuk University, Seoul 05029, 
      Republic of Korea.
FAU - Yeo, In Jun
AU  - Yeo IJ
AD  - College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk 28160, 
      Republic of Korea.
FAU - Miller, Zachary
AU  - Miller Z
AD  - Department of Pharmaceutical Sciences, University of Kentucky, 789 South 
      Limestone, Lexington, Kentucky 40536-0596, United States.
FAU - Baek, Yu Mi
AU  - Baek YM
AD  - Department of Bioscience and Biotechnology, Konkuk University, Seoul 05029, 
      Republic of Korea.
FAU - Lee, Sukyeong
AU  - Lee S
AD  - Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor 
      College of Medicine, Houston, Texas 77030, United States.
FAU - Kim, Dong-Eun
AU  - Kim DE
AUID- ORCID: 0000-0001-6545-8387
AD  - Department of Bioscience and Biotechnology, Konkuk University, Seoul 05029, 
      Republic of Korea.
FAU - Hong, Jin Tae
AU  - Hong JT
AD  - College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk 28160, 
      Republic of Korea.
FAU - Kim, Kyung Bo
AU  - Kim KB
AUID- ORCID: 0000-0003-4744-2466
AD  - Department of Pharmaceutical Sciences, University of Kentucky, 789 South 
      Limestone, Lexington, Kentucky 40536-0596, United States.
LA  - eng
GR  - R01 CA188354/CA/NCI NIH HHS/United States
GR  - R01 GM111084/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20200330
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 (Cysteine Proteinase Inhibitors)
RN  - 0 (Il1a protein, mouse)
RN  - 0 (Interleukin-1alpha)
RN  - 0 (Nootropic Agents)
RN  - 0 (Oligopeptides)
RN  - 0 (Small Molecule Libraries)
RN  - 144416-78-4 (LMP-2 protein)
RN  - EC 3.4.22.- (Cysteine Endopeptidases)
SB  - IM
MH  - Alzheimer Disease/*drug therapy
MH  - Animals
MH  - Cell Line, Transformed
MH  - Cysteine Endopeptidases/*metabolism
MH  - Cysteine Proteinase Inhibitors/chemical synthesis/*therapeutic use/toxicity
MH  - Epithelial-Mesenchymal Transition/drug effects
MH  - Humans
MH  - Interleukin-1alpha/metabolism
MH  - Mice, Transgenic
MH  - Microglia/drug effects
MH  - Molecular Structure
MH  - Nootropic Agents/chemical synthesis/*therapeutic use/toxicity
MH  - Oligopeptides/chemical synthesis/*therapeutic use/toxicity
MH  - Small Molecule Libraries/chemical synthesis/therapeutic use/toxicity
MH  - Structure-Activity Relationship
EDAT- 2020/03/20 06:00
MHDA- 2020/10/08 06:00
CRDT- 2020/03/20 06:00
PHST- 2020/03/20 06:00 [pubmed]
PHST- 2020/10/08 06:00 [medline]
PHST- 2020/03/20 06:00 [entrez]
AID - 10.1021/acs.jmedchem.0c00416 [doi]
PST - ppublish
SO  - J Med Chem. 2020 Apr 9;63(7):3763-3783. doi: 10.1021/acs.jmedchem.0c00416. Epub 
      2020 Mar 30.