Design of First-in-Class Dual EZH2/HDAC Inhibitor: Biochemical Activity and Biological Evaluation in Cancer Cells: ACS Medicinal Chemistry Letters

A. Romanelli, G. Stazi, R. Fioravanti, C. Zwergel, E. Di Bello, S. Pomella, C. Perrone, C. Battistelli, R. Strippoli, M. Tripodi, D. Del Bufalo, R. Rota, D. Trisciuoglio, A. Mai, S. Valente

Research output: Contribution to journalArticlepeer-review

Abstract

Since the histone modifying enzymes EZH2 and HDACs control a number of epigenetic-dependent carcinogenic pathways, we designed the first-in-class dual EZH2/HDAC inhibitor 5 displaying (sub)micromolar inhibition against both targets. When tested in several cancer cell lines, the hybrid 5 impaired cell viability at low micromolar level and in leukemia U937 and rhabdomyosarcoma RH4 cells provided G1 arrest, apoptotic induction, and increased differentiation, associated with an increase of acetyl-H3 and acetyl-α-tubulin and a decrease of H3K27me3 levels. In glioblastoma U87 cells, 5 hampered epithelial to mesenchymal transition by increasing the E-cadherin expression, thus proposing itself as a useful candidate for anticancer therapy. © 2020 American Chemical Society.
Original languageEnglish
Pages (from-to)977-983
Number of pages7
JournalACS Med. Chem. Lett.
Volume11
Issue number5
DOIs
Publication statusPublished - 2020

Keywords

  • anticancer agent
  • Drug discovery
  • dual-target inhibitor
  • histone deacetylase
  • histone methyltransferase
  • alpha tubulin
  • antineoplastic agent
  • histone deacetylase inhibitor
  • transcription factor EZH2
  • uvomorulin
  • alveolar rhabdomyosarcoma cell line
  • Article
  • biological activity
  • cancer cell
  • cell differentiation
  • cell viability
  • controlled study
  • drug design
  • drug screening
  • epithelial mesenchymal transition
  • G1 phase cell cycle checkpoint
  • glioblastoma cell line
  • human
  • human cell
  • priority journal
  • protein expression
  • U-937 cell line

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