A Therapeutic Perspective of HDAC8 in Different Diseases: An Overview of Selective Inhibitors

Abstract

Histone deacetylases (HDACs) are epigenetic enzymes which participate in transcriptional repression and chromatin condensation mechanisms by removing the acetyl moiety from acetylated ε-amino group of histone lysines and other non-histone proteins. In recent years, HDAC8, a class I HDAC, has emerged as a promising target for different disorders, including X-linked intellectual disability, fibrotic diseases, cancer, and various neuropathological conditions. Selective HDAC8 targeting is required to limit side effects deriving from the treatment with pan-HDAC inhibitors (HDACis); thus, many endeavours have focused on the development of selective HDAC8is. In addition, polypharmacological approaches have been explored to achieve a synergistic action on multi-factorial diseases or to enhance the drug efficacy. In this frame, proteolysis-targeting chimeras (PROTACs) might be regarded as a dual-targeting approach for attaining HDAC8 proteasomal degradation. This review highlights the most relevant and recent advances relative to HDAC8 validation in various diseases, providing a snapshot of the current selective HDAC8is, with a focus on polyfunctional modulators.

Aberrant expression of histone deacetylase 8 in endometriosis and its potential as a therapeutic target

“…Regardless, the roles of both HDAC6 and HDAC8 in various fibrotic diseases have been well‐documented 103,104 . In contrast to the therapeutic effect resulting from the inhibition of HDAC8 as demonstrated by this study, the administration of an HDAC8 activator accelerated lesional progression and fibrogenesis through promoting FMT and proliferation 72 .…”

Metalloenzyme Inhibitors against Zoonotic Infections: Focus on Leishmania and Schistosoma

“…HDACs are validated targets for the treatment of cancer and have been proposed as valuable drug targets against several diseases including antiparasitic drugs. − …”

Synthesis of N‐aminophalimides derived from α‐amino acids: Theoretical study to find them as HDAC8 inhibitors by docking simulations and in vitro assays

“…Besides, molecular docking study has also been a useful tool to design and investigate new HDAC8 inhibitors (HDAC8i) (Banerjee et al, 2019; Marek et al, 2018; Uba et al, 2019; Yang et al, 2019). In addition, HDAC8 inhibitors have been developed based on the pharmacophoric model, these molecules containing a bulky substituent such as tetrahydroisoquinoline, pyrazole, methoxyphenyl, p (prop‐2‐yn‐1‐yloxy)phenyl, p (azacyclododec‐8‐ene‐5,12‐dione)phenyl‐derived, aromatic sulphide group, 3,5‐CF 3 ‐phenyl, bulky heteroaromatic group, as a capping group (CG), an aromatic group, phenyl group linked to hydrazide or triazole, indolyl group, sulfamoyl motif, phenylamides, piperazine as a linker (LG), and ortho‐aryl N‐hydroxycinnamides, hydroxamic acid, triazole, anilide, disulphide or azetidine‐2‐one as a zinc‐binding group (ZBG) among others (Fontana et al, 2022; Huang et al, 2012; Ingham et al, 2016; Neelarapu et al, 2011; Suzuki et al, 2012; Taha et al, 2017; Tang et al, 2011; Wang & Dymock, 2009; Zhang et al, 2011, 2018).…”