Antiproliferative and apoptotic activities of sequence-specific histone acetyltransferase inhibitors

• Yu, Zutao

  Department of Chemistry, Graduate School of Science, Kyoto University

• Taniguchi, Junichi

  Department of Chemistry, Graduate School of Science, Kyoto University

• Wei, Yulei

  Department of Chemistry, Graduate School of Science, Kyoto University

• Pandian, Ganesh N.

  Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University

• Hashiya, Kaori

  Department of Chemistry, Graduate School of Science, Kyoto University

• Bando, Toshikazu

  Department of Chemistry, Graduate School of Science, Kyoto University

• Sugiyama, Hiroshi

  Department of Chemistry, Graduate School of Science, Kyoto University・Department of Chemistry, Graduate School of Science, Kyoto University

Abstract

In parallel to monomeric epigenetic regulators, sequence-specific epigenetic regulators represent versatile synthetic dual-target ligands that achieve regulatory control over multi-gene networks. Development of DNA-binding domain (DBD)-HDAC inhibitors and DBD-HAT activators, which result in increased histone acetylation, has become one promising research field. However, there is no report regarding the gene regulatory pattern by sequence-specific epigenetic repressor. We report here for the first time, the synthesis of DBD-HAT inhibitors and demonstrate that these conjugates could retain their dual-target activity using predicted working model of thermal stability assay and in vitro HAT activity assay. Evaluation of antiproliferative activity in cancer cells showed that 2 (with a medium linker length of 13-atom) exhibited the highest antiproliferative activity in p53 wild-type cancer cell lines (IC[50] of 1.8–2.6 μM in A549 and MV4-11 cells) and not in p53 mutant cancer cell lines. A mechanistic investigation using microarray analysis and an apoptotic assay showed that the antiproliferative effect of 2 occurred via the up-regulation of p53 target genes, and the subsequent initiation of p53-dependent apoptosis. Our research on sequence-specific dual-target epigenetic repressor offers us an alternative way to modulate HAT-governed therapeutically important genes and contributes to offer a fresh insight into antitumor therapeutics.

Journal

• European Journal of Medicinal Chemistry

  European Journal of Medicinal Chemistry 138 320-327, 2017-09-29

  Elsevier Masson SAS

Keywords

• Epigenetics
• Sequence specificity
• Polyamide
• HAT inhibitor
• Antiproliferation
• Apoptosis

Details

• CRID: 1050845760787602688
• NII Article ID: 120006460106
• ISSN: 02235234
• DOI: 10.1016/j.ejmech.2017.06.037
• HANDLE: 2433/230870
• Web Site: https://api.elsevier.com/content/article/PII:S022352341730483X?httpAccept=text/xml
• Web Site: https://api.elsevier.com/content/article/PII:S022352341730483X?httpAccept=text/plain
• Text Lang: en
• Article Type: journal article
• Data Source:
  • IRDB
  • Crossref
  • CiNii Articles
  • KAKEN