論文 - 詳細
| RRC ID | 57863 |
|---|---|
| 著者 | Mitsui E, Yoshida S, Shinoda Y, Matsumori Y, Tsujii H, Tsuchida M, Wada S, Hasegawa M, Ito A, Mino K, Onuki T, Yoshida M, Sasaki R, Mizukami T. |
| タイトル | Identification of ryuvidine as a KDM5A inhibitor. |
| ジャーナル | Sci Rep |
| Abstract |
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. |
| 巻・号 | 9(1) |
| ページ | 9952 |
| 公開日 | 2019-7-9 |
| DOI | 10.1038/s41598-019-46346-x |
| PII | 10.1038/s41598-019-46346-x |
| PMID | 31289306 |
| PMC | PMC6616564 |
| MeSH | Antineoplastic Agents / chemistry Antineoplastic Agents / pharmacology* Carcinoma, Non-Small-Cell Lung / drug therapy* Carcinoma, Non-Small-Cell Lung / enzymology Carcinoma, Non-Small-Cell Lung / pathology Enzyme Inhibitors / chemistry Enzyme Inhibitors / pharmacology* High-Throughput Screening Assays / methods* Humans Lung Neoplasms / drug therapy* Lung Neoplasms / enzymology Lung Neoplasms / pathology Retinoblastoma-Binding Protein 2 / antagonists & inhibitors* Small Molecule Libraries / chemistry Small Molecule Libraries / pharmacology* Tumor Cells, Cultured |
| IF | 3.998 |
| 引用数 | 0 |
| リソース情報 | |
| ヒト・動物細胞 | 293(RCB1637) |