Discovery of small-molecule positive allosteric modulators of Parkin E3 ligase.
Biochemistry
Biochemistry Applications
Chemistry
Journal
iScience
ISSN: 2589-0042
Titre abrégé: iScience
Pays: United States
ID NLM: 101724038
Informations de publication
Date de publication:
21 Jan 2022
21 Jan 2022
Historique:
received:
16
08
2021
revised:
03
11
2021
accepted:
10
12
2021
entrez:
13
1
2022
pubmed:
14
1
2022
medline:
14
1
2022
Statut:
epublish
Résumé
Pharmacological activation of the E3 ligase Parkin represents a rational therapeutic intervention for the treatment of Parkinson's disease. Here we identify several compounds that enhance the activity of wildtype Parkin in the presence of phospho-ubiquitin and act as positive allosteric modulators (PAMs). While these compounds activate Parkin in a series of biochemical assays, they do not act by thermally destabilizing Parkin and fail to enhance the Parkin translocation rate to mitochondria or to enact mitophagy in cell-based assays. We conclude that in the context of the cellular milieu the therapeutic window to pharmacologically activate Parkin is very narrow.
Identifiants
pubmed: 35024585
doi: 10.1016/j.isci.2021.103650
pii: S2589-0042(21)01620-5
pmc: PMC8733272
doi:
Types de publication
Journal Article
Langues
eng
Pagination
103650Informations de copyright
© 2021 The Author(s).
Déclaration de conflit d'intérêts
All authors are employees and shareholders at Biogen.
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