Abstract
Histone deacetylase (HDAC) enzymes play crucial roles in epigenetic gene expression and are an attractive therapeutic target. Five HDAC inhibitors have been approved for cancer treatment to date, however, clinical applications have been limited due to poor single-agent drug efficacy and side effects associated with a lack of HDAC isoform or complex selectivity. An emerging strategy aiming to address these limitations is the development of bifunctional HDAC therapeutics—single molecules comprising a HDAC inhibitor conjugated to another specificity targeting moiety. This review summarises the recent advancements in novel types of dual-targeting HDAC modulators, including proteolysis-targeting chimeras (PROTACs), with a focus on HDAC isoform and complex selectivity, and the future potential of such bifunctional molecules in achieving enhanced drug efficacy and therapeutic benefits in treating disease.
Highlights
The reversible acetylation and deacetylation of protein substrates play critical roles in the regulation of epigenetic gene expression and other cellular processes [1,2,3,4]
It can be seen with the twelve-carbon linker, 35, Von Hippel–Lindau (VHL) and HDAC2 are brought into close proximity with no direct steric clash or protein–protein overlap, unlike the six-carbon linker, 36, suggesting that if 36 is cell permeable, it may be unable to form the necessary ternary complex required for polyubiquitination and degradation
The FDA approval of five Histone deacetylase (HDAC) inhibitors has firmly established the importance of HDACs as achieve improved efficacy and selectivity profiles
Summary
The reversible acetylation and deacetylation of protein substrates play critical roles in the regulation of epigenetic gene expression and other cellular processes [1,2,3,4]. Despite mediating the acetylation status of various proteins, the zinc-dependent HDACs possess inhibitors encompass a generic three-part “cap–linker–zinc binding group” pharmacophore model a mostly conserved catalytic active site (Figure 1b) [16,17], the majority of synthesised HDAC (Figure 1c) [18]. Linker which mimics the substrate lysine side fitting the 11 Å oftenchannel containsleading aromatic with residues the outer region of the active site or tube-like tomoieties the zincthat ion,interact plus maintaining thenear multiple hydrophobic interactions within on the protein external surface. The inhibitorsthe arealiphatic categorised concentrations, causing cycle arrest and apoptosis cultured2)cells [20] Basedacids on their zinc-binding group; structural similarities seenselectivity. The o-aminoanilides, referred to as benzamides, exhibit high class-I selectivity, as do the cyclic peptides [21]
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