Abstract
Histone deacetylases (HDACs) remove acetyl groups from acetylated lysine residues and have a large variety of substrates and interaction partners. Therefore, it is not surprising that HDACs are involved in many diseases. Most inhibitors of zinc-dependent HDACs (HDACis) including approved drugs contain a hydroxamate as a zinc-binding group (ZBG), which is by far the biggest contributor to affinity, while chemical variation of the residual molecule is exploited to create more or less selectivity against HDAC isozymes or other metalloproteins. Hydroxamates have a propensity for nonspecificity and have recently come under considerable suspicion because of potential mutagenicity. Therefore, there are significant concerns when applying hydroxamate-containing compounds as therapeutics in chronic diseases beyond oncology due to unwanted toxic side effects. In the last years, several alternative ZBGs have been developed, which can replace the critical hydroxamate group in HDACis, while preserving high potency. Moreover, these compounds can be developed into highly selective inhibitors. This review aims at providing an overview of the progress in the field of non-hydroxamic HDACis in the time period from 2015 to present. Formally, ZBGs are clustered according to their binding mode and structural similarity to provide qualitative assessments and predictions based on available structural information.
Highlights
Histone deacetylases (HDACs) belong to the machinery of the epigenetic apparatus and play a crucial role in chromatin remodeling by altering posttranscriptional modifications and controlling gene transcription, which is maladjusted in various cancers, leading to altered transcription of onco- and tumor suppressor genes [1]
Hydroxamic acids constitute by far the largest group of Histone deacetylase inhibitors (HDACis) due to their pronounced capability to form high-affinity chelates with the catalytic zinc ion at the bottom of the active site
This review provides an overview about recent developments toward potent and selective HDACis lacking the widely represented hydroxamate zinc-binding group (ZBG)
Summary
Histone deacetylases (HDACs) belong to the machinery of the epigenetic apparatus and play a crucial role in chromatin remodeling by altering posttranscriptional modifications and controlling gene transcription, which is maladjusted in various cancers, leading to altered transcription of onco- and tumor suppressor genes [1]. Histone deacetylase inhibitors (HDACis) exhibit a wide range of cytotoxic effects and facilitate hyperacetylation, permitting the transcription and activation of genes such as p53, p21Waf/Cip, Gadd 45, FAS, and caspase-3, which are associated with cell-cycle arrest, differentiation, and apoptosis [4,5,6,7,8,9] This possible therapeutic potential of HDACs has attracted increasing attention for the specified reason and because of the ability to deacetylate non-histone proteins that are commonly involved in cancer metabolism [10,11,12,13,14]. ZBGs are clustered according to their binding mode and structural similarity to provide qualitative assessments and predictions based on available structural information
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