Design of first-in-class dual EZH2/HDAC inhibitor: biochemical activity and biological evaluation in cancer cells
01 Pubblicazione su rivista
Romanelli Annalisa, Stazi Giulia, Fioravanti Rossella, Zwergel Clemens, Di Bello Elisabetta, Pomella Silvia, Perrone Clara, Battistelli Cecilia, Strippoli Raffaele, Tripodi Marco, del Bufalo Donatella, Rota Rossella, Trisciuoglio Daniela, Mai Antonello, Valente Sergio
ISSN: 1948-5875
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.