Identification of ryuvidine as a KDM5A inhibitor

• Published in: Scientific reports 2019-07, Vol.9 (1), p.9952-10, Article 9952
• Main Authors: Mitsui, Eishin, Yoshida, Shogo, Shinoda, Yui, Matsumori, Yasumasa, Tsujii, Hiroshi, Tsuchida, Mie, Wada, Shuichi, Hasegawa, Makoto, Ito, Akihiro, Mino, Koshiki, Onuki, Tetsuo, Yoshida, Minoru, Sasaki, Ryuzo, Mizukami, Tamio
• Format: Article
• Language: English
• Subjects: 631/154/1435/2163; 631/67/1059/602; 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; Demethylation; DNA methylation; Drug dosages; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzymes; Epigenetics; Gefitinib; High-Throughput Screening Assays - methods; Humanities and Social Sciences; Humans; LSD; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - enzymology; Lung Neoplasms - pathology; Lysergic acid diethylamide; multidisciplinary; Peptides; Reporter gene; Retinoblastoma-Binding Protein 2 - antagonists & inhibitors; Science; Science (multidisciplinary); Small cell lung carcinoma; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Tumor Cells, Cultured
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-46346-x

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.