Novel inhibitors of lysine (K)-specific Demethylase 4A with anticancer activity.
Hyo Jeong LeeBo-Kyoung KimKyoung Bin YoonYong-Chul KimSun-Young HanPublished in: Investigational new drugs (2017)
Lysine (K)-specific demethylase 4A (KDM4A) is a histone demethylase that removes methyl residues from trimethylated or dimethylated histone 3 at lysines 9 and 36. Overexpression of KDM4A is found in various cancer types. To identify KDM4A inhibitors with anti-tumor functions, screening with an in vitro KDM4A enzyme activity assay was carried out. The benzylidenehydrazine analogue LDD2269 was selected, with an IC50 of 6.56 μM of KDM4A enzyme inhibition, and the binding mode was investigated using in silico molecular docking. Demethylation inhibition by LDD2269 was confirmed with a cell-based assay using antibodies against methylated histone at lysines 9 and 36. HCT-116 colon cancer cell line proliferation was suppressed by LDD2269, which also interfered with soft-agar growth and migration of HCT-116 cells. AnnexinV staining and PARP cleavage experiments showed apoptosis induction by LDD2269. Derivatives of LDD2269 were synthesized and the structure-activity relationship was explored. LDD2269 is reported here as a strong inhibitor of KDM4A in in vitro and cell-based systems, with anti-tumor functions.
Keyphrases
- molecular docking
- cell cycle arrest
- structure activity relationship
- dna methylation
- cell death
- single cell
- high throughput
- cell therapy
- signaling pathway
- induced apoptosis
- molecular dynamics simulations
- cell proliferation
- dna damage
- stem cells
- gene expression
- mass spectrometry
- transcription factor
- mesenchymal stem cells
- dna repair
- atomic force microscopy
- binding protein
- flow cytometry
- single molecule