Identification of histone deacetylase inhibitors with (arylidene)aminoxy scaffold active in uveal melanoma cell lines

Published on Jan 1, 2021in Journal of Enzyme Inhibition and Medicinal Chemistry4.673
· DOI :10.1080/14756366.2020.1835883
Susanna Nencetti18
Estimated H-index: 18
(UniPi: University of Pisa),
Doretta Cuffaro5
Estimated H-index: 5
(UniPi: University of Pisa)
+ 11 AuthorsElisabetta Orlandini20
Estimated H-index: 20
(UniPi: University of Pisa)
Sources
Abstract
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.
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