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14.09.2017 | PRECLINICAL STUDIES | Ausgabe 6/2017

Investigational New Drugs 6/2017

Novel inhibitors of lysine (K)-specific Demethylase 4A with anticancer activity

Zeitschrift:
Investigational New Drugs > Ausgabe 6/2017
Autoren:
Hyo Jeong Lee, Bo-Kyoung Kim, Kyoung Bin Yoon, Yong-Chul Kim, Sun-Young Han
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1007/​s10637-017-0496-2) contains supplementary material, which is available to authorized users.
Hyo Jeong Lee and Bo-Kyoung Kim contributed equally to the work.

Summary

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.

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ESM 1 (DOCX 61 kb)
10637_2017_496_MOESM1_ESM.docx
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