Selective Targeting of Epigenetic Readers and Histone Deacetylases in Autoimmune and Inflammatory Diseases: Recent Advances and Future Perspectives

Abstract

Histone deacetylases (HDACs) and bromodomain-containing proteins (BCPs) play a key role in chromatin remodeling. Based on their ability to regulate inducible gene expression in the context of inflammation and cancer, HDACs and BCPs have been the focus of drug discovery efforts, and numerous small-molecule inhibitors have been developed. However, dose-limiting toxicities of the first generation of inhibitors, which typically target multiple HDACs or BCPs, have limited translation to the clinic. Over the last decade, an increasing effort has been dedicated to designing class-, isoform-, or domain-specific HDAC or BCP inhibitors, as well as developing strategies for cell-specific targeted drug delivery. Selective inhibition of the epigenetic modulators is helping to elucidate the functions of individual epigenetic proteins and has the potential to yield better and safer therapeutic strategies. In accordance with this idea, several in vitro and in vivo studies have reported the ability of more selective HDAC/BCP inhibitors to recapitulate the beneficial effects of pan-inhibitors with less unwanted adverse events. In this review, we summarize the most recent advances with these strategies, discussing advantages and limitations of these approaches as well as some therapeutic perspectives, focusing on autoimmune and inflammatory diseases.

New Insight in HDACs: Potential Therapeutic Targets for the Treatment of Atherosclerosis

“…These issues need to be addressed in future research works. HDACi has been extensively studied in recent years and has been regarded to have a potential therapeutic effect on many diseases, including neurodegenerative diseases, autoimmune diseases, acute graft-versus-host disease, and so on ( Vojinovic et al, 2011 ; Ghiboub et al, 2021 ). Its potential therapeutic effect on AS is also worth exploring through further research.…”

Bromodomain (BrD) Family Members as Regulators of Cancer Stemness—A Comprehensive Review

“…The hydrophobic nature of the Kac-binding pocket of the BrD and the fact that the strength of this BrD-Kac interaction is relatively low make these domains, particularly targetable by small molecules. In several BrD members, the BrD modules are present in multiples (i.e., PBR1 encodes 6 BrDs), while in most BrD proteins, the bromodomain is linked via flexible sequences to diverse interaction or catalytic domains resulting in a high divergence of a BrD protein family [ 8 , 26 , 27 , 28 ].…”

Modulation of macrophage inflammatory function through selective inhibition of the epigenetic reader protein SP140

“…The experiment was performed in duplicate. (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20), Biotinylated H3 and Biotinylated H3 (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). (e) SP140-NL and Histone3.3-HT DNA were transfected into HEK293 cells.…”

“…Since Brd and PHD domains are capable of binding to histones, this suggests that SP140 might function as an epigenetic reader. Readers are recruited to chromatin possessing specific epigenetic "marks" and regulate gene expression through mechanisms that modulate DNA accessibility to transcription factors (TFs) and the transcriptional machinery [19,20]. Brds are tractable to small molecule antagonists, with selective inhibitors of several Brd-containing proteins (BCPs) reported [20,21].…”

“…Readers are recruited to chromatin possessing specific epigenetic "marks" and regulate gene expression through mechanisms that modulate DNA accessibility to transcription factors (TFs) and the transcriptional machinery [19,20]. Brds are tractable to small molecule antagonists, with selective inhibitors of several Brd-containing proteins (BCPs) reported [20,21]. Such compounds have helped elucidate the function of their BCP targets; for instance, multiple inhibitors targeting BRD2, BRD3, and BRD4 have been used to demonstrate the role of these proteins in selectively regulating gene expression in the context of cancer and inflammation [9,22,23].…”