Activity-Guided Design of HDAC11-Specific Inhibitors

Son, Se In; Cao, Ji; Zhu, Chengliang; Miller, Seth P.; Lin, Hening

doi:10.1021/acschembio.9b00292

Cited by 52 publications

(63 citation statements)

References 30 publications

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“…Future investigations are needed to identify HDAC11 defatty-acylated substrates and to dissect the molecular mechanisms between HDAC11 and metabolism. Interestingly, HDAC11 activity can be inhibited by new and more selective drugs [60,61], which could open avenues for the development of new therapies for the treatment of chronic muscle metabolic diseases.…”

Section: Discussionmentioning

confidence: 99%

HDAC11 is a novel regulator of fatty acid oxidative metabolism in skeletal muscle

et al. 2020

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Skeletal muscle is the largest tissue in mammalian organisms and is a key determinant of basal metabolic rate and whole‐body energy metabolism. Histone deacetylase 11 (HDAC11) is the only member of the class IV subfamily of HDACs, and it is highly expressed in skeletal muscle, but its role in skeletal muscle physiology has never been investigated. Here, we describe for the first time the consequences of HDAC11 genetic deficiency in skeletal muscle, which results in the improvement of muscle function enhancing fatigue resistance and muscle strength. Loss of HDAC11 had no obvious impact on skeletal muscle structure but increased the number of oxidative myofibers by promoting a glycolytic‐to‐oxidative muscle fiber switch. Unexpectedly, HDAC11 was localized in muscle mitochondria and its deficiency enhanced mitochondrial content. In particular, we showed that HDAC11 depletion increased mitochondrial fatty acid β‐oxidation through activating the AMP‐activated protein kinase‐acetyl‐CoA carboxylase pathway and reducing acylcarnitine levels in vivo, thus providing a mechanistic explanation for the improved muscle strength and fatigue resistance. Overall, our data reveal a unique role of HDAC11 in the maintenance of muscle fiber‐type balance and the mitochondrial lipid oxidation. These findings shed light on the mechanisms governing muscle metabolism and may have implications for chronic muscle metabolic disease management.

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Section: Discussionmentioning

confidence: 99%

HDAC11 is a novel regulator of fatty acid oxidative metabolism in skeletal muscle

et al. 2020

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“…For example, replacement of the hydroxamic acid ZBG of the selective HDAC6 inhibitor tubastatin A with an N ‐propylhydrazide group switched its selectivity toward class I HDACs; HDAC1‐3. On the other hand, N ‐alkylhydrazides with longer alkyl groups demonstrated exceptionally good selectivity for the sole member of class IV HDACs, HDAC11, as shown by Son et al [68] . Their best inhibitor SIS17, an n‐palmitoyl substituted thiophenecarbohydrazide, had an IC 50 value of 0.8 μM on HDAC11 while showing no significant inhibition of HDAC1, HDAC4 and HDAC8 at 100 μM.…”

Section: Strategies To Design Selective Hdac Inhibitorsmentioning

confidence: 95%

Strategies To Design Selective Histone Deacetylase Inhibitors

et al. 2021

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This review classifies drug‐design strategies successfully implemented in the development of histone deacetylase (HDAC) inhibitors, which have many applications including cancer treatment. Our focus is on especially demanded selective HDAC inhibitors and their structure‐activity relationships in relation to corresponding protein structures. The main part of the paper is divided into six subsections each narrating how optimization of one of six structural features can influence inhibitor selectivity. It starts with the impact of the zinc binding group on selectivity, continues with the optimization of the linker placed in the substrate binding tunnel as well as the adjustment of the cap group interacting with the surface of the protein, and ends with the addition of groups targeting class‐specific sub‐pockets: the side‐pocket‐, lower‐pocket‐ and foot‐pocket‐targeting groups. The review is rounded off with a conclusion and an outlook on the future of HDAC inhibitor design.

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“…This effect leads to type I interferon receptor chain 1 (IFNαR1) polyubiquitylation and degradation, as well as downregulation of IFN signaling ( Cao et al, 2019 ). HDAC11-specific inhibitors, such as elevenostat, FT895, and SIS17, might represent promising future treatments that target lipid metabolic dysregulation in cancers ( Martin et al, 2018 ; Kutil et al, 2019 ; Son et al, 2019 ). SIRT3 has a role in mitochondrial fatty-acid β-oxidation by regulating long-chain acyl-CoA dehydrogenase (LCAD) ( Hirschey et al, 2010 ).…”

Section: Biological Functions Of Hdacsmentioning

confidence: 99%

The Roles of Histone Deacetylases and Their Inhibitors in Cancer Therapy

Guo

Tian

Zhu

2020

Front. Cell Dev. Biol.

199

135

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Genetic mutations and abnormal gene regulation are key mechanisms underlying tumorigenesis. Nucleosomes, which consist of DNA wrapped around histone cores, represent the basic units of chromatin. The fifth amino group (N ε) of histone lysine residues is a common site for post-translational modifications (PTMs), and of these, acetylation is the second most common. Histone acetylation is modulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs), and is involved in the regulation of gene expression. Over the past two decades, numerous studies characterizing HDACs and HDAC inhibitors (HDACi) have provided novel and exciting insights concerning their underlying biological mechanisms and potential anti-cancer treatments. In this review, we detail the diverse structures of HDACs and their underlying biological functions, including transcriptional regulation, metabolism, angiogenesis, DNA damage response, cell cycle, apoptosis, protein degradation, immunity and other several physiological processes. We also highlight potential avenues to use HDACi as novel, precision cancer treatments.

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Activity-Guided Design of HDAC11-Specific Inhibitors

Cited by 52 publications

References 30 publications

HDAC11 is a novel regulator of fatty acid oxidative metabolism in skeletal muscle

HDAC11 is a novel regulator of fatty acid oxidative metabolism in skeletal muscle

Strategies To Design Selective Histone Deacetylase Inhibitors

The Roles of Histone Deacetylases and Their Inhibitors in Cancer Therapy

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