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Review
. 2023;4(4):757-779.
doi: 10.37349/etat.2023.00166. Epub 2023 Aug 31.

Medicinal chemistry advances in targeting class I histone deacetylases

Diaaeldin I Abdallah  1   2 , Elvin D de Araujo  1 , Naman H Patel  1 , Lina S Hasan  1 , Richard Moriggl  3 , Oliver H Krämer  4 , Patrick T Gunning  1   2
Affiliations
Review

Medicinal chemistry advances in targeting class I histone deacetylases

Diaaeldin I Abdallah et al. Explor Target Antitumor Ther. 2023.

Abstract

Histone deacetylases (HDACs) are a class of zinc (Zn)-dependent metalloenzymes that are responsible for epigenetic modifications. HDACs are largely associated with histone proteins that regulate gene expression at the DNA level. This tight regulation is controlled by acetylation [via histone acetyl transferases (HATs)] and deacetylation (via HDACs) of histone and non-histone proteins that alter the coiling state of DNA, thus impacting gene expression as a downstream effect. For the last two decades, HDACs have been studied extensively and indicated in a range of diseases where HDAC dysregulation has been strongly correlated with disease emergence and progression-most prominently, cancer, neurodegenerative diseases, HIV, and inflammatory diseases. The involvement of HDACs as regulators in these biochemical pathways established them as an attractive therapeutic target. This review summarizes the drug development efforts exerted to create HDAC inhibitors (HDACis), specifically class I HDACs, with a focus on the medicinal chemistry, structural design, and pharmacology aspects of these inhibitors.

Keywords: Histone deacetylases; cap group; epigenetic regulation; medicinal chemistry; small-molecule inhibitors; zinc-binding group.

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Conflict of interest statement

The authors declare that they have no conflicts of interest.

Figures

Figure 1
Figure 1
The basic principle of acetylation status for open (euchromatin) or closed chromatin (heterochromatin). Structural organization of DNA wrapped around histone proteins, and the effects on expression of proteins such as TSG transcription due to the downregulation of HATs and upregulation of HDACs during oncogenic activity in the cell. Acetylation of histones on surface exposed Lys residues by HAT. Histone acetylation yields an amide that is neutral at physiological pH and thus weakly interacts with the negatively charged DNA, thus allowing the cellular transcription machinery to access TSGs for transcription. Deacetylation of histones by HDAC. Histone deacetylation yields a primary amine that is positively charged at physiological pH and thus strongly interacts with the negatively charged DNA, thus preventing the cellular transcription machinery (ie. RNAPII) from accessing TSGs for transcription. HDACi aid in the inhibition of HDAC activity. The figure was created with Biorender.com. RNAPII: RNA polymerase II; CoA: coenzyme A; Ac: acetyl; HDACi: HDAC inhibitor
Figure 2
Figure 2
HDAC catalytic tunnel architecture. (A) Catalytic tunnels of HDAC1 (grey) and HDAC2 (red) superimposed; (B) catalytic tunnels of HDAC1 (grey) and HDAC3 (green) superimposed; (C) catalytic tunnels of HDAC2 (red) and HDAC3 (green) superimposed; (D) catalytic tunnels of HDAC1 (grey) and HDAC8 (gold) superimposed; (E) catalytic tunnels of HDAC2 (red) and HDAC8 (gold) superimposed; (F) catalytic tunnels of HDAC3 (red) and HDAC8 (gold) superimposed. Zn atoms are represented as spheres with the corresponding protein mesh surface colors. All images were generated via Maestro according to the PDB codes as detailed in Table 1
Figure 3
Figure 3
General class I HDACi pharmacophore
Figure 4
Figure 4
HDACi pharmacophore and chemotypes with juxtaposition to the critical Zn2+ ion. (A) Different chemotypes of ZBGs used to target class I HDACs with intramolecular hydrogen bonding patterns; (B) ZBGs coordinating to Zn2+
Figure 5
Figure 5
Lossen’s rearrangement. The mechanism through a chemical reaction called Lossen’s rearrangement is depicted, exemplified by a general hydroxamate through which the isocyanate intermediate forms, causing DNA mutagenesis and eventual toxicity [41]
Figure 6
Figure 6
Pan-HDACi overview. (A) Broadly acting pan-HDACs bearing a hydroxamate ZBG that exhibit target engagement towards class I HDACs; (B) inhibitors bearing a hydroxamate ZBG that are HDAC8-selective [–49]; (C) potential “cis” conformations adopted by HDAC8-selective inhibitors [43]. * Asterisks refer to inhibitors that are either clinical candidates or FDA-approved drugs. SI: selectivity index; Ki: inhibition constant
Figure 7
Figure 7
Examples of class I HDACi [–57]. * Asterisks refer to inhibitors that are either clinical candidates or FDA-approved drugs
Figure 8
Figure 8
Structural presentation of class I HDAC catalytic centers. Class I HDAC tunnels surrounded by hydrophobic Phe residues. (A) HDAC1 (grey mesh) surrounded by Phe150 (in front of the tunnel in the image) and Phe205 (behind the tunnel in the image); (B) HDAC2 (red mesh) surrounded by Phe155 (in front of the tunnel in the image) and Phe210 (behind the tunnel in the image); (C) HDAC3 (green mesh) surrounded by Phe144 (in front of the tunnel in the image) and Phe199 and Phe200 (behind and to the side of the tunnel in the image); (D) HDAC8 (gold mesh) surrounded by Phe152 (in front of the tunnel in the image), Phe207, and Phe208 (behind and to the side of the tunnel in the image). All images in this figure were generated by Maestro
Figure 9
Figure 9
Structural presentation of the HDAC2 catalytic center. HDAC2 catalytic tunnel (PDB: 3MAX) labeled with HDACi binding moieties [58, 59]
Figure 10
Figure 10
Examples of selective HDAC1/2 inhibitors [, –64]
Figure 11
Figure 11
Examples of selective HDAC3 inhibitors [–69]
Figure 12
Figure 12
Examples of HDAC3 selective inhibitors [–74]
Figure 13
Figure 13
Overview of the chemical reaction of belinostat transformation. Transformation of belinostat to belinostat glucuronide in phase II metabolism [–77]
Figure 14
Figure 14
Examples of hydrazide HDACis [–83]
Figure 15
Figure 15
Examples of HDACi with thiols as ZBGs [–87]. (A) IC50 values for enzymatic inhibition of different HDAC isozymes and (B) examples of processes that generate thiols out of their respective prodrugs (disulfide bridges/thioesters) [85]. * Asterisks refer to inhibitors that are either clinical candidates or FDA-approved drugs
Figure 16
Figure 16
Examples of recently discovered novel ZBGs [–91]
See this image and copyright information in PMC

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