Inhibitors of heat shock protein 70 (Hsp70) with enhanced metabolic stability reduce tau levels.
Hsc70
Hsp72
Metabolism
Molecular chaperone
Neurodegeneration
Protein folding
Tauopathy
Journal
Bioorganic & medicinal chemistry letters
ISSN: 1464-3405
Titre abrégé: Bioorg Med Chem Lett
Pays: England
ID NLM: 9107377
Informations de publication
Date de publication:
01 06 2021
01 06 2021
Historique:
received:
22
11
2020
revised:
30
03
2021
accepted:
04
04
2021
pubmed:
12
4
2021
medline:
18
9
2021
entrez:
11
4
2021
Statut:
ppublish
Résumé
The molecular chaperone, Heat Shock Protein 70 (Hsp70), is an emerging drug target for neurodegenerative diseases, because of its ability to promote degradation of microtubule-associated protein tau (MAPT/tau). Recently, we reported YM-08 as a brain penetrant, allosteric Hsp70 inhibitor, which reduces tau levels. However, the benzothiazole moiety of YM-08 is vulnerable to metabolism by CYP3A4, limiting its further application as a chemical probe. In this manuscript, we designed and synthesized seventeen YM-08 derivatives by systematically introducing halogen atoms to the benzothiazole ring and shifting the position of the heteroatom in a distal pyridine. In microsome assays, we found that compound JG-23 has 12-fold better metabolic stability and it retained the ability to reduce tau levels in two cell-based models. These chemical probes of Hsp70 are expected to be useful tools for studying tau homeostasis.
Identifiants
pubmed: 33839251
pii: S0960-894X(21)00251-1
doi: 10.1016/j.bmcl.2021.128025
pmc: PMC8805511
mid: NIHMS1774016
pii:
doi:
Substances chimiques
Benzothiazoles
0
HSP70 Heat-Shock Proteins
0
Thiazolidines
0
YM-08 compound
0
tau Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
128025Subventions
Organisme : NINDS NIH HHS
ID : R01 NS059690
Pays : United States
Informations de copyright
Copyright © 2021 Elsevier Ltd. All rights reserved.
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