The Effect of Various Zinc Binding Groups on Inhibition of Histone Deacetylases 1–11

Abstract

Histone deacetylases (HDACs) have the ability to cleave the acetyl groups of ε-N-acetylated lysine residues in a variety of proteins. Given that human cells contain thousands of different acetylated lysine residues, HDACS may regulate a wide variety of processes including some implicated in conditions such as cancer and neurodegenerative disorders. Herein we report the synthesis and in vitro biochemical profiling of a series of compounds, including known inhibitors as well as novel chemotypes, that incorporate putative new zinc binding domains. By evaluating the compound collection against all 11 recombinant human HDACs, we found that the trifluoromethyl ketone functionality provides potent inhibition of all four subclasses of the Zn(2+) -dependent HDACs. Potent inhibition was observed with two different scaffolds, demonstrating the efficiency of the trifluoromethyl ketone moiety as a zinc binding motif. Interestingly, we also identified silanediol as a zinc binding group with potential for future development of non-hydroxamate class I and class IIb HDAC inhibitors.

Assessment of the Allelochemical Activity and Biochemical Profile of Different Phenotypes of Picocyanobacteria from the Genus Synechococcus

“…Furthermore, the most abundant substance in Synechococcus Type 3a was proven to be silanediol, which has protease inhibitor properties [40]. Moreover, studies conducted by Madsen et al [41] have proven that silanediols represent a novel zinc binding group (ZBG) with properties that can be used for the development of histone deacetylase inhibitors, which have an important role inter alia in apoptosis [42].…”

Developing drugs targeting transition metal homeostasis

“…Small molecular inhibitors of histone deacetylases (HDACs) are in clinical trials for the anticancer activity. These inhibitors target HDACs by chelating zinc at the active site, and research continues into altering the affinity of the zinc-binding moiety, to tune the selectivity of the inhibitors [28,29]. …”

A Fluorescence‐Lifetime‐Based Binding Assay for Class IIa Histone Deacetylases

“…The development of the assay was inspired by a binding assay for class I and IIb HDACs that involves a ligand probe containing a hydroxamate group. In this study, a series of DBD probes with a trifluoromethyl ketone (TFMK) pharmacophoric group instead of a hydroxamic acid were synthesised, because compounds containing a TFMK group have been described as reasonable ligands for class IIa HDACs …”

“…The presented assay was further exploited to determine the affinity of a set of HDAC inhibitors by using a competitive binding assay . Unfortunately, these probes are not applicable to class IIa HDACs as hydroxamic acids are known to be mostly weak inhibitors of these enzymes . In fact, before now, there was no direct binding assay for HDAC class IIa enzymes, although the molecular recognition of acetylated lysine residues is supposed to be their primary mode of action.…”