The therapeutic hope for HDAC6 inhibitors in malignancy and chronic disease

Abstract

Recent years have witnessed an emergence of a new class of therapeutic agents, termed histone deacetylase 6 (HDAC6) inhibitors. HDAC6 is one isoform of a family of HDAC enzymes that catalyse the removal of functional acetyl groups from proteins. It stands out from its cousins in almost exclusively deacetylating cytoplasmic proteins, in exerting deacetylation-independent effects and in the success that has been achieved in developing relatively isoform-specific inhibitors of its enzymatic action that have reached clinical trial. HDAC6 plays a pivotal role in the removal of misfolded proteins and it is this role that has been most successfully targeted to date. HDAC6 inhibitors are being investigated for use in combination with proteasome inhibitors for the treatment of lymphoid malignancies, whereby HDAC6-dependent protein disposal currently limits the cytotoxic effectiveness of the latter. Similarly, numerous recent studies have linked altered HDAC6 activity to the pathogenesis of neurodegenerative diseases that are characterized by misfolded protein accumulation. It seems likely though that the function of HDAC6 is not limited to malignancy and neurodegeneration, the deacetylase being implicated in a number of other cellular processes and diseases including in cardiovascular disease, inflammation, renal fibrosis and cystogenesis. Here, we review the unique features of HDAC6 that make it so appealing as a drug target and its currently understood role in health and disease. Whether HDAC6 inhibition will ultimately find a clinical niche in the treatment of malignancy or prevalent complex chronic diseases remains to be determined.

HDAC6 – An Emerging Target against Chronic Myeloid Leukemia?

“…Several studies have demonstrated the influence of HDAC6 in neurodegenerative, cardiovascular and renal diseases, as well as in inflammation [175] and viral response [84]. The role of the HDAC6 protein in cancer is also now well better understood.…”

Radiosynthesis and preliminary evaluation of an18F‐labeled tubastatin A analog for PET imaging of histone deacetylase 6

“…5 Acetylation of lysine residues in the N-termini of histones neutralizes their positive charge, which weakens the interaction between histones and negatively charged DNA, thereby allowing enhanced accessibility of transcription factors to the DNA. [7][8][9][10][11] For instance, suberoylanilide hydroxamic acid (SAHA, also known as vorinostat) is a nonselective HDAC inhibitor that is the first US Food and Drug Administrationapproved hydroxamic acid-based drug for use in patients with cutaneous T-cell lymphoma. [7][8][9][10][11] For instance, suberoylanilide hydroxamic acid (SAHA, also known as vorinostat) is a nonselective HDAC inhibitor that is the first US Food and Drug Administrationapproved hydroxamic acid-based drug for use in patients with cutaneous T-cell lymphoma.…”

“…6 Abnormalities in such epigenetic regulatory system are important factors in the development of diseases including cancer and neurodegeneration; therefore, HDACs are considered promising therapeutic targets for these diseases. [7][8][9][10][11] For instance, suberoylanilide hydroxamic acid (SAHA, also known as vorinostat) is a nonselective HDAC inhibitor that is the first US Food and Drug Administrationapproved hydroxamic acid-based drug for use in patients with cutaneous T-cell lymphoma. 3 HDAC6, which belongs to the class IIb, is a unique member because of its characteristic localization and functions.…”

“…35 Due to the characteristics of HDAC6, selective imaging of HDAC6 could facilitate research into its roles in cancers and neurodegenerative diseases. Regarding the development of HDAC6-selective radioligands, Lu et al reported on 11 C-carbonylation methods for labeling tubastatin A, an HDAC6-selective inhibitor (1 in Figure 1), 36 that employed [ 11 C]carbon monoxide. 37 Radiosynthesis of the tubastatin A analog [ 11 C]KB631 ([ 11 C]2 in Figure 1) with [ 11 C]methyl iodide was also reported by Lu et al, 38 and its preclinical evaluation for visualization of B16F10 melanoma has recently been reported by Vermeulen et al 39 Additionally, [ 18 F] Bavarostat was developed by Strebl et al 40 as an adamantane-conjugated HDAC6-selective radioligand.…”

Baseline HDAC6 and TFF3 proteins overexpression as prognostic markers of lupus nephritis relapse

“…Histone deacetylases (HDACs) are enzymes that play an integral role in several cellular processes by extracting the acetyl group from histone or non-histone proteins (5). Based on their homology to yeast orthologous, mammalian HDACs are classified into 4 classes: I (HDACs1, 2, 3, and 8), II (HDACs 4, 5, 6, 7, 9, and 10), III (SIRT1-7), and IV (HDAC11) (6). Histone deacetylase 6 (HDAC6) is a cytoplasmic protein that regulates several cellular processes through deacetylasedependent and/or deacetylase-independent mechanisms.…”