HDAC6 is an enzyme that regulates a variety of biological pathways in dividing cells, but also in... more HDAC6 is an enzyme that regulates a variety of biological pathways in dividing cells, but also in post-mitotic neurons. In these cells, different cellular functions and survival are dependent on HDAC6-mediated processes such as intracellular trafficking, antioxidation, chaperone-mediated stress responses, and protein degradation. As a consequence, the interest in HDAC6 as a potential target to treat several neurodegenerative disorders has grown significantly over the last decade. This review summarizes the current knowledge on the interaction partners and functions of HDAC6 as well as the most important arguments for its involvement in several neurodegenerative diseases. As many of these disorders are hallmarked by alterations in HDAC6-mediated pathways, it is hypothesized that HDAC6 could play a pivotal role in the pathophysiology of neurodegeneration. HDAC6-dependent deacetylation of its substrates could result in neurotoxicity, while the ubiquitin-dependent functions of HDAC6 could be essential for neuroprotection. Therefore, targeting the deacetylating activity of HDAC6, while leaving its other functions unhampered, might be an interesting strategy to treat neurodegenerative disorders.
Charcot-Marie-Tooth (CMT) disease is a disorder of the peripheral nervous system where progressiv... more Charcot-Marie-Tooth (CMT) disease is a disorder of the peripheral nervous system where progressive degeneration of motor and sensory nerves leads to motor problems and sensory loss and for which no pharmacological treatment is available. Recently, it has been shown in a model for the axonal form of CMT that histone deacetylase 6 (HDAC6) can serve as a target for the development of a pharmacological therapy. Therefore, we aimed at developing new selective and activity-specific HDAC6 inhibitors with improved biochemical properties. By utilizing a bicyclic cap as the structural scaffold from which to build upon, we developed several analogues that showed improved potency compared to tubastatin A while maintaining excellent selectivity compared to HDAC1. Further screening in N2a cells examining both the acetylation of α-tubulin and histones narrowed down the library of compounds to three potent and selective HDAC6 inhibitors. In mutant HSPB1-expressing DRG neurons, serving as an in vitr...
The synthesis of novel isoform-selective HDAC inhibitors is considered to be an important, emergi... more The synthesis of novel isoform-selective HDAC inhibitors is considered to be an important, emerging field in medicinal chemistry. In this paper, the preparation and assessment of thirteen selective HDAC6 inhibitors is disclosed, elaborating on a previously developed thiaheterocyclic Tubathian series. All compounds were evaluated in vitro for their ability to inhibit HDAC6, and a selection of five potent compounds was further screened toward all HDAC isoforms (HDAC1-11). The capability of these Tubathian analogs to inhibit α-tubulin deacetylation was assessed as well, and ADME/Tox data were collected. This thorough SAR evaluation revealed that the oxidized, para-substituted hydroxamic acids can be recognized as valuable lead structures in the pursuit of novel potent and selective HDAC6 inhibitors.
The International Journal of Biochemistry & Cell Biology, 2012
Charcot-Marie-Tooth disease is the most common inherited disorder of the peripheral nervous syste... more Charcot-Marie-Tooth disease is the most common inherited disorder of the peripheral nervous system. The disease is characterized by a progressive muscle weakness and atrophy, sensory loss, foot (and hand) deformities and steppage gait. While many of the genes associated with axonal CMT have been identified, to date it is unknown which mechanism(s) causes the disease. However, genetic findings indicate that the underlying mechanisms mainly converge to the axonal cytoskeleton. In this review, we will summarize the evidence for this pathogenic convergence. Furthermore, recent work with new transgenic mouse models has led to the identification of histone deacetylase 6 as a potential therapeutic target for inherited peripheral neuropathies. This enzyme deacetylates microtubules and plays a crucial role in the regulation of axonal transport. These findings offer new perspectives for a potential therapy to treat axonal Charcot-Marie-Tooth disease and other neurodegenerative disorders characterized by axonal transport defects.
HDAC6 is an enzyme that regulates a variety of biological pathways in dividing cells, but also in... more HDAC6 is an enzyme that regulates a variety of biological pathways in dividing cells, but also in post-mitotic neurons. In these cells, different cellular functions and survival are dependent on HDAC6-mediated processes such as intracellular trafficking, antioxidation, chaperone-mediated stress responses, and protein degradation. As a consequence, the interest in HDAC6 as a potential target to treat several neurodegenerative disorders has grown significantly over the last decade. This review summarizes the current knowledge on the interaction partners and functions of HDAC6 as well as the most important arguments for its involvement in several neurodegenerative diseases. As many of these disorders are hallmarked by alterations in HDAC6-mediated pathways, it is hypothesized that HDAC6 could play a pivotal role in the pathophysiology of neurodegeneration. HDAC6-dependent deacetylation of its substrates could result in neurotoxicity, while the ubiquitin-dependent functions of HDAC6 could be essential for neuroprotection. Therefore, targeting the deacetylating activity of HDAC6, while leaving its other functions unhampered, might be an interesting strategy to treat neurodegenerative disorders.
A small library of 3-[(4-hydroxycarbamoylphenyl)aminomethyl]benzothiophenes was prepared and asse... more A small library of 3-[(4-hydroxycarbamoylphenyl)aminomethyl]benzothiophenes was prepared and assessed as a novel class of HDAC6 inhibitors, leading to the identification of three representatives as potent and selective HDAC6 inhibitors. Further tests with regard to inflammatory responses indicated that HDAC6 inhibition can be uncoupled from transcriptional inhibition at the level of activated NF-κB, AP-1, and GR.
HDAC6 is an enzyme that regulates a variety of biological pathways in dividing cells, but also in... more HDAC6 is an enzyme that regulates a variety of biological pathways in dividing cells, but also in post-mitotic neurons. In these cells, different cellular functions and survival are dependent on HDAC6-mediated processes such as intracellular trafficking, antioxidation, chaperone-mediated stress responses, and protein degradation. As a consequence, the interest in HDAC6 as a potential target to treat several neurodegenerative disorders has grown significantly over the last decade. This review summarizes the current knowledge on the interaction partners and functions of HDAC6 as well as the most important arguments for its involvement in several neurodegenerative diseases. As many of these disorders are hallmarked by alterations in HDAC6-mediated pathways, it is hypothesized that HDAC6 could play a pivotal role in the pathophysiology of neurodegeneration. HDAC6-dependent deacetylation of its substrates could result in neurotoxicity, while the ubiquitin-dependent functions of HDAC6 could be essential for neuroprotection. Therefore, targeting the deacetylating activity of HDAC6, while leaving its other functions unhampered, might be an interesting strategy to treat neurodegenerative disorders.
Charcot-Marie-Tooth (CMT) disease is a disorder of the peripheral nervous system where progressiv... more Charcot-Marie-Tooth (CMT) disease is a disorder of the peripheral nervous system where progressive degeneration of motor and sensory nerves leads to motor problems and sensory loss and for which no pharmacological treatment is available. Recently, it has been shown in a model for the axonal form of CMT that histone deacetylase 6 (HDAC6) can serve as a target for the development of a pharmacological therapy. Therefore, we aimed at developing new selective and activity-specific HDAC6 inhibitors with improved biochemical properties. By utilizing a bicyclic cap as the structural scaffold from which to build upon, we developed several analogues that showed improved potency compared to tubastatin A while maintaining excellent selectivity compared to HDAC1. Further screening in N2a cells examining both the acetylation of α-tubulin and histones narrowed down the library of compounds to three potent and selective HDAC6 inhibitors. In mutant HSPB1-expressing DRG neurons, serving as an in vitr...
The synthesis of novel isoform-selective HDAC inhibitors is considered to be an important, emergi... more The synthesis of novel isoform-selective HDAC inhibitors is considered to be an important, emerging field in medicinal chemistry. In this paper, the preparation and assessment of thirteen selective HDAC6 inhibitors is disclosed, elaborating on a previously developed thiaheterocyclic Tubathian series. All compounds were evaluated in vitro for their ability to inhibit HDAC6, and a selection of five potent compounds was further screened toward all HDAC isoforms (HDAC1-11). The capability of these Tubathian analogs to inhibit α-tubulin deacetylation was assessed as well, and ADME/Tox data were collected. This thorough SAR evaluation revealed that the oxidized, para-substituted hydroxamic acids can be recognized as valuable lead structures in the pursuit of novel potent and selective HDAC6 inhibitors.
The International Journal of Biochemistry & Cell Biology, 2012
Charcot-Marie-Tooth disease is the most common inherited disorder of the peripheral nervous syste... more Charcot-Marie-Tooth disease is the most common inherited disorder of the peripheral nervous system. The disease is characterized by a progressive muscle weakness and atrophy, sensory loss, foot (and hand) deformities and steppage gait. While many of the genes associated with axonal CMT have been identified, to date it is unknown which mechanism(s) causes the disease. However, genetic findings indicate that the underlying mechanisms mainly converge to the axonal cytoskeleton. In this review, we will summarize the evidence for this pathogenic convergence. Furthermore, recent work with new transgenic mouse models has led to the identification of histone deacetylase 6 as a potential therapeutic target for inherited peripheral neuropathies. This enzyme deacetylates microtubules and plays a crucial role in the regulation of axonal transport. These findings offer new perspectives for a potential therapy to treat axonal Charcot-Marie-Tooth disease and other neurodegenerative disorders characterized by axonal transport defects.
HDAC6 is an enzyme that regulates a variety of biological pathways in dividing cells, but also in... more HDAC6 is an enzyme that regulates a variety of biological pathways in dividing cells, but also in post-mitotic neurons. In these cells, different cellular functions and survival are dependent on HDAC6-mediated processes such as intracellular trafficking, antioxidation, chaperone-mediated stress responses, and protein degradation. As a consequence, the interest in HDAC6 as a potential target to treat several neurodegenerative disorders has grown significantly over the last decade. This review summarizes the current knowledge on the interaction partners and functions of HDAC6 as well as the most important arguments for its involvement in several neurodegenerative diseases. As many of these disorders are hallmarked by alterations in HDAC6-mediated pathways, it is hypothesized that HDAC6 could play a pivotal role in the pathophysiology of neurodegeneration. HDAC6-dependent deacetylation of its substrates could result in neurotoxicity, while the ubiquitin-dependent functions of HDAC6 could be essential for neuroprotection. Therefore, targeting the deacetylating activity of HDAC6, while leaving its other functions unhampered, might be an interesting strategy to treat neurodegenerative disorders.
A small library of 3-[(4-hydroxycarbamoylphenyl)aminomethyl]benzothiophenes was prepared and asse... more A small library of 3-[(4-hydroxycarbamoylphenyl)aminomethyl]benzothiophenes was prepared and assessed as a novel class of HDAC6 inhibitors, leading to the identification of three representatives as potent and selective HDAC6 inhibitors. Further tests with regard to inflammatory responses indicated that HDAC6 inhibition can be uncoupled from transcriptional inhibition at the level of activated NF-κB, AP-1, and GR.
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Papers by Veronick Benoy