Journal
INVESTIGATIONAL NEW DRUGS
Volume 35, Issue 6, Pages 733-741Publisher
SPRINGER
DOI: 10.1007/s10637-017-0496-2
Keywords
KDM4A; Demethylase; Anti-cancer agent
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Funding
- National Research Foundation (NRF) - Ministry of Science, ICT & Future Planning [2015R1C1A2A01053928]
- National Research Foundation of Korea [2015R1C1A2A01053928] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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 mu M 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.
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