Open AccessDesign of First-in-Class Dual EZH2/HDAC Inhibitor: Biochemical Activity and Biological Evaluation in Cancer Cells
Author(s) -
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,
Sérgio Valente
Publication year - 2020
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.0c00014
Subject(s) - ezh2 , cancer research , epigenetics , cancer cell , acetylation , cancer , cell culture , histone h3 , chemistry , biology , biochemistry , genetics , gene
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.