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

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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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Author notes

  1. Hyo Jeong Lee and Bo-Kyoung Kim contributed equally to the work.

Authors and Affiliations

  1. College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, 501 Jinju-daero, Jinju, Gyeongnam, 52828, Republic of Korea

    Hyo Jeong Lee, Kyoung Bin Yoon & Sun-Young Han

  2. School of Life Sciences, Gwangju Institute of Science & Technology, 123 Cheomdangwagi-ro, Buk-gu, Gwangju, 61005, Republic of Korea

    Bo-Kyoung Kim & Yong-Chul Kim

  3. New Drug Development Center (NDDC), Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu, Republic of Korea

    Bo-Kyoung Kim

Authors
  1. Hyo Jeong Lee
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  2. Bo-Kyoung Kim
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  3. Kyoung Bin Yoon
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  4. Yong-Chul Kim
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  5. Sun-Young Han
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Correspondence to Yong-Chul Kim or Sun-Young Han.

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The authors declare that they have no conflict of interest.

Funding

This research was supported by Basic Science Research Program through the National Research Foundation (NRF) funded by the Ministry of Science, ICT & Future Planning (2015R1C1A2A01053928).

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This article does not contain any studies with human participants or animals.

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Lee, H.J., Kim, BK., Yoon, K.B. et al. Novel inhibitors of lysine (K)-specific Demethylase 4A with anticancer activity. Invest New Drugs 35, 733–741 (2017). https://doi.org/10.1007/s10637-017-0496-2

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  • DOI: https://doi.org/10.1007/s10637-017-0496-2

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