Recent advances in the discovery of potent and selective HDAC6 inhibitors

Wang, Xiuxiu; Wan, R.; Liu, Zhaopeng

doi:10.1016/j.ejmech.2017.10.040

Cited by 127 publications

(93 citation statements)

References 84 publications

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“…While most previous studies have utilized tubacin to inhibit HDAC6, other inhibitors have been recently developed with better pharmacological properties (Wang et al 2017). These HDAC6-selective inhibitors have been shown to ameliorate disease phenotypes in mouse models of Alzheimer's disease (Zhang et al 2014), Charcot-Marie-Tooth disease (Benoy et al 2017), and in cell culture models of Huntington's disease (Guedes-Dias et al 2015) and tauopathy (Cook et al 2014), confirming earlier findings.…”

Section: Neurotoxic Roles For Hdac6supporting

confidence: 71%

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Complex neuroprotective and neurotoxic effects of histone deacetylases

Thomas

D’Mello

2018

Journal of Neurochemistry

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By their ability to shatter quality of life for both patients and caregivers, neurodegenerative diseases are the most devastating of human disorders. Unfortunately, there are no effective or long-terms treatments capable of slowing down the relentless loss of neurons in any of these diseases. One impediment is the lack of detailed knowledge of the molecular mechanisms underlying the processes of neurodegeneration. While some neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, are mostly sporadic in nature, driven by both environment and genetic susceptibility, many others, including Huntington's disease, spinocerebellar ataxias, and spinal-bulbar muscular atrophy, are genetically inherited disorders. Surprisingly, given their different roots and etiologies, both sporadic and genetic neurodegenerative disorders have been linked to disease mechanisms involving histone deacetylase (HDAC) proteins, which consists of 18 family members with diverse functions. While most studies have implicated certain HDAC subtypes in promoting neurodegeneration, a substantial body of literature suggests that other HDAC proteins can preserve neuronal viability. Of particular interest, however, is the recent realization that a single HDAC subtype can have both neuroprotective and neurotoxic effects. Diverse mechanisms, beyond transcriptional regulation have been linked to these effects, including deacetylation of non-histone proteins, protein-protein interactions, post-translational modifications of the HDAC proteins themselves and direct interactions with disease proteins. The roles of these HDACs in both sporadic and genetic neurodegenerative diseases will be discussed in the current review.

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Section: Neurotoxic Roles For Hdac6supporting

confidence: 71%

“…While most previous studies have utilized tubacin to inhibit HDAC6, other inhibitors have been recently developed with better pharmacological properties (Wang et al . ). These HDAC6‐selective inhibitors have been shown to ameliorate disease phenotypes in mouse models of Alzheimer's disease (Zhang et al .…”

Section: Hdac6mentioning

confidence: 97%

Complex neuroprotective and neurotoxic effects of histone deacetylases

Thomas

D’Mello

2018

Journal of Neurochemistry

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“…Despite the observation of a moderate overexpression of the HDAC6 protein in urothelial cancerous tissues, the inhibition of the protein had limited efficacy compared to the use of inhibitors targeting several HDACs [176]. On the other hand, the inhibition of HDAC6 has notable anti-cancer properties in the context of multiple myeloma [177], chronic lymphocytic leukemia [114], and acute myeloid leukemia [178], as well as solid cancers including prostate cancer [137], breast cancer [179], melanoma [139], and ovarian cancer [102]. Here, we will focus on the involvement of HDAC6 in CML.…”

Section: Hdac6 In CMLmentioning

confidence: 99%

HDAC6 – An Emerging Target against Chronic Myeloid Leukemia?

Losson

Schnekenburger

Dicato

et al. 2020

Preprint

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Imatinib became the standard treatment for chronic myeloid leukemia (CML) about 20 years ago, which was a major breakthrough in stabilizing the pathology and improving the quality of life of patients. However, the emergence of resistance to imatinib and other tyrosine kinase inhibitors leads researchers to characterize new therapeutic targets. Several studies have highlighted the role of histone deacetylase 6 (HDAC6) in various pathologies, including cancer. This protein effectively intervenes in cellular activities by its primarily cytoplasmic localization. In this review, we will discuss the molecular characteristics of the HDAC6 protein, as well as its overexpression in CML leukemic stem cells, which make it a promising therapeutic target for the treatment of CML.Keywords: histone deacetylase 6 inhibitor; personalized treatment; heat shock protein 90α; leukemia stem cells; imatinib resistance; targeted therapy Preprints (www.preprints.org) | NOT PEER-REVIEWED |

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“…In hematological malignancies, HDAC6 has been reported to be overexpressed in both B- and T-cell lymphomas [61] and its inhibition has demonstrated activity in preclinical models of lymphomas and MM [135,136]. Different HDAC6 selective inhibitors have been synthesized, and most of them belong to the class of hydroxamic acids [137,138] (Table 4). Small molecules such as tubacin and tubastatin have been developed to target HDAC6 [42,139].…”

Section: Anticancer Effects Of Hdac Inhibitors and Their Roles In mentioning

confidence: 99%

The Therapeutic Strategy of HDAC6 Inhibitors in Lymphoproliferative Disease

Cosenza

Pozzi

2018

IJMS

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Histone deacetylases (HDACs) are master regulators of chromatin remodeling, acting as epigenetic regulators of gene expression. In the last decade, inhibition of HDACs has become a target for specific epigenetic modifications related to cancer development. Overexpression of HDAC has been observed in several hematologic malignancies. Therefore, the observation that HDACs might play a role in various hematologic malignancies has brought to the development of HDAC inhibitors as potential antitumor agents. Recently, the class IIb, HDAC6, has emerged as one potential selective HDACi. This isoenzyme represents an important pharmacological target for selective inhibition. Its selectivity may reduce the toxicity related to the off-target effects of pan-HDAC inhibitors. HDAC6 has also been studied in cancer especially for its ability to coordinate a variety of cellular processes that are important for cancer pathogenesis. HDAC6 has been reported to be overexpressed in lymphoid cells and its inhibition has demonstrated activity in preclinical and clinical study of lymphoproliferative disease. Various studies of HDAC6 inhibitors alone and in combination with other agents provide strong scientific rationale for the evaluation of these new agents in the clinical setting of hematological malignancies. In this review, we describe the HDACs, their inhibitors, and the recent advances of HDAC6 inhibitors, their mechanisms of action and role in lymphoproliferative disorders.

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Recent advances in the discovery of potent and selective HDAC6 inhibitors

Cited by 127 publications

References 84 publications

Complex neuroprotective and neurotoxic effects of histone deacetylases

Complex neuroprotective and neurotoxic effects of histone deacetylases

HDAC6 – An Emerging Target against Chronic Myeloid Leukemia?

The Therapeutic Strategy of HDAC6 Inhibitors in Lymphoproliferative Disease

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Recent advances in the discovery of potent and selective HDAC6 inhibitors

Cited by 127 publications

References 84 publications

Complex neuroprotective and neurotoxic effects of histone deacetylases

Complex neuroprotective and neurotoxic effects of histone deacetylases

HDAC6 &ndash; An Emerging Target against Chronic Myeloid Leukemia?

The Therapeutic Strategy of HDAC6 Inhibitors in Lymphoproliferative Disease

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Product

Resources

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HDAC6 – An Emerging Target against Chronic Myeloid Leukemia?