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Design of First-in-Class Dual EZH2/HDAC Inhibitor: Biochemical Activity and Biological Evaluation in Cancer Cells
journal contribution
posted on 2020-03-26, 13:41 authored by 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 ValenteSince 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.
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H 3K levelscancer cell linesG 1 arrestrhabdomyosarcoma RH 4 cellsHDACs controlBiochemical Activityenzymes EZH 2E-cadherin expressionBiological Evaluationmesenchymal transitionCancer Cellsacetyl -α-tubulinleukemia U 937anticancer therapymicromolar levelglioblastoma U 87 cellsapoptotic inductionacetyl-H 3cell viability
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