Therapeutic Potential of CKD-504, a Novel Selective Histone Deacetylase 6 Inhibitor, in a Zebrafish Model of Neuromuscular Junction Disorders

Jeong, Hui Su; Kim, Hye J.; Kim, Deok Ho; Chung, Ki Wha; Choi, Byung Ok; Lee, Ji Eun

doi:10.14348/molcells.2022.5005

Cited by 9 publications

(4 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, except for ACY-1215, the present application range of other HDAC6 inhibitors is limited. Studies on ACY-241 ( Ray et al, 2018 ; Cosenza et al, 2020 ; Awad et al, 2021 ; Park et al, 2021 ) and KA2507 ( Tsimberidou et al, 2021 ) mainly focused on tumors, CKD-504 ( Choi et al, 2020 ; Ha et al, 2020 ; Jeong et al, 2022 ; Smith et al, 2022 ) focused on neurological diseases, and CKD-506 ( Choi et al, 2018 ; Park et al, 2020 ; Bae et al, 2021 ) focused on inflammatory diseases. Although ACY-241 and KA2507 show higher selectivity over ACY-1215 on HDAC6, its studies on other diseases needs further research ( Table 3 ).…”

Section: Future Perspectivementioning

confidence: 99%

Role of Selective Histone Deacetylase 6 Inhibitor ACY-1215 in Cancer and Other Human Diseases

et al. 2022

Front. Pharmacol.

View full text Add to dashboard Cite

The deacetylation process regulated by histone deacetylases (HDACs) plays an important role in human health and diseases. HDAC6 belongs to the Class IIb of HDACs family, which mainly modifies non-histone proteins located in the cytoplasm. HDAC6 plays a key role in tumors, neurological diseases, and inflammatory diseases. Therefore, targeting HDAC6 has become a promising treatment strategy in recent years. ACY-1215 is the first orally available highly selective HDAC6 inhibitor, and its efficacy and therapeutic effects are being continuously verified. This review summarizes the research progress of ACY-1215 in cancer and other human diseases, as well as the underlying mechanism, in order to guide the future clinical trials of ACY-1215 and more in-depth mechanism researches.

show abstract

Section: Future Perspectivementioning

confidence: 99%

Role of Selective Histone Deacetylase 6 Inhibitor ACY-1215 in Cancer and Other Human Diseases

et al. 2022

Front. Pharmacol.

View full text Add to dashboard Cite

show abstract

“…In zebrafish, SV2 (synaptic vesicle protein 2) staining reveals synaptic vesicles in motor axons and terminals; thus, staining has been 2D) are opposed to postsynaptic α-BTX (bungarotoxin)-stained AChR clusters (red in Fig. 2D) [36,37]. We found that hRAB40B-Y83X-transformant zebrafish were labeled less often by both pre-and postsynaptic markers in the larval NMJs (Fig.…”

Section: Transient Transformation With Human Rab40b-y83x Induced Moti...mentioning

confidence: 79%

“…2D ) are opposed to postsynaptic α-BTX (bungarotoxin)-stained AChR clusters (red in Fig. 2D ) [ 36 , 37 ]. We found that hRAB40B-Y83X -transformant zebrafish were labeled less often by both pre- and postsynaptic markers in the larval NMJs ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Peripheral Neuropathy and Decreased Locomotion of a RAB40B Mutation in Human and Model Animals

Son,

Jeong,

Nam

et al. 2023

Exp Neurobiol

Self Cite

View full text Add to dashboard Cite

Rab40 proteins are an atypical subgroup of Rab GTPases containing a unique suppressor of the cytokine signaling (SOCS) domain that is recruited to assemble the CRL5 E3 ligase complex for proteolytic regulation in various biological processes. A nonsense mutation deleting the C-terminal SOCS box in the RAB40B gene was identified in a family with axonal peripheral neuropathy (Charcot-Marie-Tooth disease type 2), and pathogenicity of the mutation was assessed in model organisms of zebrafish and Drosophila . Compared to control fish, zebrafish larvae transformed by the human mutant hRAB40B-Y83X showed a defective swimming pattern of stalling with restricted localization and slower motility. We were consistently able to observe reduced labeling of synaptic markers along neuromuscular junctions of the transformed larvae. In addition to the neurodevelopmental phenotypes, compared to normal hRAB40B expression, we further examined ectopic expression of hRAB40B-Y83X in Drosophila to show a progressive decline of locomotion ability. Decreased ability of locomotion by ubiquitous expression of the human mutation was reproduced not with GAL4 drivers for neuron-specific expression but only when a pan-glial GAL4 driver was applied. Using the ectopic expression model of Drosophila , we identified a genetic interaction in which Cul5 down regulation exacerbated the defective motor performance, showing a consistent loss of SOCS box of the pathogenic RAB40B. Taken together, we could assess the possible gain-of-function of the human RAB40B mutation by comparing behavioral phenotypes in animal models; our results suggest that the mutant phenotypes may be associated with CRL5-mediated proteolytic regulation.

show abstract

“…Electrophysiologic misfiring and axonal transport defects are corrected in CMT2D motor neurons by tubastatin A and CKD-504 (124). Tubastatin A and CKD-504 improve deficient neurite outgrowth and defective neuromuscular junction maturation that are observed in zebrafish embryos where Gars is knocked down with splice-blocking antisense morpholino oligonucleotides (125).…”

Section: Multi-modal and Multi-indication Therapeutics For Motor Neur...mentioning

confidence: 99%

Biological networks and complexity in early-onset motor neuron diseases

Butchbach

Scott

2022

Front. Neurol.

View full text Add to dashboard Cite

Motor neuron diseases (MNDs) are neuromuscular disorders where the spinal motor neurons–either the cell bodies themselves or their axons–are the primary cells affected. To date, there are 120 different genes that are lost or mutated in pediatric-onset MNDs. Most of these childhood-onset disorders, aside from spinal muscular atrophy (SMA), lack viable therapeutic options. Previous research on MNDs has focused on understanding the pathobiology of a single, specific gene mutation and targeting therapies to that pathobiology. This reductionist approach has yielded therapeutic options for a specific disorder, in this case SMA. Unfortunately, therapies specific for SMA have not been effective against other pediatric-onset MNDs. Pursuing the same approach for the other defined MNDs would require development of at least 120 independent treatments raising feasibility issues. We propose an alternative to this this type of reductionist approach by conceptualizing MNDs in a complex adaptive systems framework that will allow identification of common molecular and cellular pathways which form biological networks that are adversely affected in early-onset MNDs and thus MNDs with similar phenotypes despite diverse genotypes. This systems biology approach highlights the complexity and self-organization of the motor system as well as the ways in which it can be affected by these genetic disorders. Using this integrated approach to understand early-onset MNDs, we would be better poised to expand the therapeutic repertoire for multiple MNDs.

show abstract

Therapeutic Potential of CKD-504, a Novel Selective Histone Deacetylase 6 Inhibitor, in a Zebrafish Model of Neuromuscular Junction Disorders

Cited by 9 publications

References 51 publications

Role of Selective Histone Deacetylase 6 Inhibitor ACY-1215 in Cancer and Other Human Diseases

Role of Selective Histone Deacetylase 6 Inhibitor ACY-1215 in Cancer and Other Human Diseases

Peripheral Neuropathy and Decreased Locomotion of a RAB40B Mutation in Human and Model Animals

Biological networks and complexity in early-onset motor neuron diseases

Contact Info

Product

Resources

About