Imidazopyridines as Potent KDM5 Demethylase Inhibitors Promoting Reprogramming Efficiency of Human iPSCs.
Biochemistry
Biological Sciences
Molecular Biology
Journal
iScience
ISSN: 2589-0042
Titre abrégé: iScience
Pays: United States
ID NLM: 101724038
Informations de publication
Date de publication:
22 Feb 2019
22 Feb 2019
Historique:
received:
21
09
2018
revised:
11
12
2018
accepted:
08
01
2019
pubmed:
28
1
2019
medline:
28
1
2019
entrez:
28
1
2019
Statut:
ppublish
Résumé
Pioneering human induced pluripotent stem cell (iPSC)-based pre-clinical studies have raised safety concerns and pinpointed the need for safer and more efficient approaches to generate and maintain patient-specific iPSCs. One approach is searching for compounds that influence pluripotent stem cell reprogramming using functional screens of known drugs. Our high-throughput screening of drug-like hits showed that imidazopyridines-analogs of zolpidem, a sedative-hypnotic drug-are able to improve reprogramming efficiency and facilitate reprogramming of resistant human primary fibroblasts. The lead compound (O4I3) showed a remarkable OCT4 induction, which at least in part is due to the inhibition of H3K4 demethylase (KDM5, also known as JARID1). Experiments demonstrated that KDM5A, but not its homolog KDM5B, serves as a reprogramming barrier by interfering with the enrichment of H3K4Me3 at the OCT4 promoter. Thus our results introduce a new class of KDM5 chemical inhibitors and provide further insight into the pluripotency-related properties of KDM5 family members.
Identifiants
pubmed: 30685712
pii: S2589-0042(19)30012-4
doi: 10.1016/j.isci.2019.01.012
pmc: PMC6354736
pii:
doi:
Types de publication
Journal Article
Langues
eng
Pagination
168-181Informations de copyright
Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.
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