TY - JOUR
T1 - Identification of histone deacetylase inhibitors with (arylidene)aminoxy scaffold active in uveal melanoma cell lines
AU - Nencetti, Susanna
AU - Cuffaro, Doretta
AU - Nuti, Elisa
AU - Ciccone, Lidia
AU - Rossello, Armando
AU - Fabbi, Marina
AU - Ballante, Flavio
AU - Ortore, Gabriella
AU - Carbotti, Grazia
AU - Campelli, Francesco
AU - Banti, Irene
AU - Gangemi, Rosaria
AU - Marshall, Garland R.
AU - Orlandini, Elisabetta
N1 - Funding Information:
This study was partially supported by the University of Pisa [PRA_2017_51], by the Italian Ministry of University and Research (MIUR) [FFABR-2017] (S.N.), by the Italian Ministry of Health (5 ? 1000 funds 2015, M.F.), and National Institutes of Health (NIH) [5R01GM106974] (G.R.M.). The authors wish to thank Dr. M. J. Jager, Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands, for the kind gift of UM cell lines.
Publisher Copyright:
© 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2021/1/1
Y1 - 2021/1/1
N2 - Uveal melanoma (UM) represents an aggressive type of cancer and currently, there is no effective treatment for this metastatic disease. In the last years, histone deacetylase inhibitors (HDACIs) have been studied as a possible therapeutic treatment for UM, alone or in association with other chemotherapeutic agents. Here we synthesised a series of new HDACIs based on the SAHA scaffold bearing an (arylidene)aminoxy moiety. Their HDAC inhibitory activity was evaluated on isolated human HDAC1, 3, 6, and 8 by fluorometric assay and their binding mode in the catalytic site of HDACs was studied by molecular docking. The most promising hit was the quinoline derivative VS13, a nanomolar inhibitor of HDAC6, which exhibited a good antiproliferative effect on UM cell lines at micromolar concentration and a capability to modify the mRNA levels of HDAC target genes similar to that of SAHA.
AB - Uveal melanoma (UM) represents an aggressive type of cancer and currently, there is no effective treatment for this metastatic disease. In the last years, histone deacetylase inhibitors (HDACIs) have been studied as a possible therapeutic treatment for UM, alone or in association with other chemotherapeutic agents. Here we synthesised a series of new HDACIs based on the SAHA scaffold bearing an (arylidene)aminoxy moiety. Their HDAC inhibitory activity was evaluated on isolated human HDAC1, 3, 6, and 8 by fluorometric assay and their binding mode in the catalytic site of HDACs was studied by molecular docking. The most promising hit was the quinoline derivative VS13, a nanomolar inhibitor of HDAC6, which exhibited a good antiproliferative effect on UM cell lines at micromolar concentration and a capability to modify the mRNA levels of HDAC target genes similar to that of SAHA.
KW - (arylidene)aminoxy-based hydroxamates
KW - HDAC inhibitors
KW - HDAC6
KW - SAHA
KW - Uveal melanoma
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U2 - 10.1080/14756366.2020.1835883
DO - 10.1080/14756366.2020.1835883
M3 - Article
C2 - 33100043
AN - SCOPUS:85094650168
VL - 36
SP - 34
EP - 47
JO - Journal of Enzyme Inhibition and Medicinal Chemistry
JF - Journal of Enzyme Inhibition and Medicinal Chemistry
SN - 1475-6366
IS - 1
ER -