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

Annalisa Romanelli, Giulia Stazi, Rossella Fioravanti, Clemens Zwergel, Elisabetta Di Bello, Silvia Pomella, Clara Perrone, Cecilia Battistelli, Raffaele Strippoli, Marco Tripodi, Donatella Del Bufalo, Rossella Rota, Daniela Trisciuoglio, Antonello Mai, Sergio Valente

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)977-983
Number of pages7
JournalACS Medicinal Chemistry Letters
Volume11
Issue number5
DOIs
Publication statusPublished - May 14 2020

Keywords

  • anticancer agent
  • Drug discovery
  • dual-target inhibitor
  • histone deacetylase
  • histone methyltransferase

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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