Histone deacetylases (HDACs) regulate gene expression by modulating chromatin architecture
via histone hypoacetylation. They play a key role in regulating cellular processes including cell
cycle arrest and apoptosis. Hyperactivity of HDACs plays a key role in tumour onset and progression
making these enzymes as striking targets for anticancer drugs and therapy. Certain cancers are associated
with upregulation of specific class II HDAC isoform rather than multiple ones. Therapeutic intervention
using small-molecules namely histone deacetylase inhibitors (HDACi), often targets many
isoforms unselectively (pan-HDACi) due to structural identity culminating in debilitating off-target effects
and reduced in vivo potency. This emphasizes the escalating need for developing isoform-selective inhibitors against
the defined class of HDACs. Despite the safe and elevated therapeutic benefit, the design of such inhibitors has been challenging.
The present article provides intricate details about the role of class II HDAC isoforms in fuelling distinct cancers
and the current challenges with the use of pan-HDAC inhibitors in anticancer therapy. The article also highlights the diverse
synthetic and in silico approaches taken by scientific community towards the designing of isoform-selective inhibitors
against class II HDAC isoforms. The strategies discussed in this review will provide further impetus to the ongoing
research regarding the designing of isoform-selective inhibitors for safe and effective anticancer therapy which is today’s
Keywords: Histone deacetylases, Histone deacetylase inhibitors, Pan-inhibitors, Isoform-selective inhibitors, Cancer.
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