Identification of ryuvidine as a KDM5A inhibitor.
Antineoplastic Agents
/ chemistry
Carcinoma, Non-Small-Cell Lung
/ drug therapy
Enzyme Inhibitors
/ chemistry
High-Throughput Screening Assays
/ methods
Humans
Lung Neoplasms
/ drug therapy
Retinoblastoma-Binding Protein 2
/ antagonists & inhibitors
Small Molecule Libraries
/ chemistry
Tumor Cells, Cultured
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
09 07 2019
09 07 2019
Historique:
received:
23
04
2019
accepted:
26
06
2019
entrez:
11
7
2019
pubmed:
11
7
2019
medline:
4
11
2020
Statut:
epublish
Résumé
KDM5 family members (A, B, C and D) that demethylate H3K4me3 have been shown to be involved in human cancers. Here we performed screening for KDM5A inhibitors from chemical libraries using the AlphaScreen method and identified a battery of screening hits that inhibited recombinant KDM5A. These compounds were further subjected to cell-based screening using a reporter gene that responded to KDM5A inhibition and 6 compounds were obtained as candidate inhibitors. When further confirmation of their inhibition activity on cellular KDM5A was made by immunostaining H3K4me3 in KDM5A-overexpressing cells, ryuvidine clearly repressed H3K4me3 demethylation. Ryuvidine prevented generation of gefitinib-tolerant human small-cell lung cancer PC9 cells and also inhibited the growth of the drug-tolerant cells at concentrations that did not affect the growth of parental PC9 cells. Ryuvidine inhibited not only KDM5A but also recombinant KDM5B and C; KDM5B was the most sensitive to the inhibitor. These results warrant that ryuvidine may serve as a lead compound for KDM5 targeted therapeutics.
Identifiants
pubmed: 31289306
doi: 10.1038/s41598-019-46346-x
pii: 10.1038/s41598-019-46346-x
pmc: PMC6616564
doi:
Substances chimiques
Antineoplastic Agents
0
Enzyme Inhibitors
0
Small Molecule Libraries
0
KDM5A protein, human
EC 1.14.11.-
Retinoblastoma-Binding Protein 2
EC 1.14.11.27
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
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