Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: unknown
Published: Dec. 16, 2024
Acute liver injury is a severe and potentially life-threatening condition. Currently, there are no specific effective treatments available. HDAC6 has been identified as promising strategy for treating ALI by inhibiting necrosis inflammation. In this study, series of pyrazole derivatives were designed to specifically target HDAC6, among which compound
Language: Английский
The Prostate, Journal Year: 2024, Volume and Issue: unknown
Published: Feb. 20, 2024
Abstract Background Metastatic castration‐resistant prostate cancer (CRPC), the most refractory cancer, inevitably progresses and becomes unresponsive to hormone therapy, revealing a pressing unmet need for this disease. Novel agents targeting HDAC6 microtubule dynamics can be potential anti‐CRPC strategy. Methods Cell proliferation was examined in CRPC PC‐3 DU‐145 cells using sulforhodamine B assay anchorage‐dependent colony formation assay. Flow cytometric analysis of propidium iodide staining used determine cell‐cycle progression. Cell‐based tubulin polymerization confocal immunofluorescence microscopic examination assembly/disassembly status. Protein expressions were determined Western blot analysis. Results A total 82 novel derivatives designed synthesized, Compound 25202 stood out, showing highest efficacy blocking (IC 50 , 3.5 nM enzyme assay; IC 1.0 μM antiproliferative cells), superior tubastatin 5.4 assay). The selectivity superiority validated by examining acetylation both α‐tubulin histone H3, detecting cell apoptosis HDACs activity assessment. Notably, but not significantly decreased protein expression. prolonged mitotic arrest through detection cyclin B1 upregulation, Cdk1 activation, phosphoprotein levels, Bcl‐2 phosphorylation. did mimic docetaxel inducing disrupted organization. also increased phosphorylation CDC20, BUB1, BUBR1, indicating activation spindle assembly checkpoint (SAC). Moreover, profoundly sensitized cisplatin‐induced death impairment cisplatin‐evoked DNA damage response repair ATR–Chk1 ATM–Chk2 pathways. Conclusion data suggest that is selective potent inhibitor. blocks interferes dynamics, leading SAC prolongation eventually cause cells. Furthermore, sensitizes impeding
Language: Английский
Citations
2
Frontiers in Oncology, Journal Year: 2022, Volume and Issue: 12
Published: Nov. 15, 2022
Gastric cancer is a common gastrointestinal cancer. Survival outcome for patients with the recurrence or metastasis remains poor due to lack of effective targeting drugs. The mechanisms non-histone acetylation modifications are key epigenetic regulations that participate in various biological processes. HDAC6 mostly located cytoplasm deacetylate substrates, which has been identified as critical promoter many oncogenic pathways cancers, including gastric Nevertheless, its inhibitor not applied clinically. In this study, we canagliflozin an active HDAC6-targeted from FDA-approved Drug Library by enzymatic assay. strong affinity compounds was further verified surface plasmon resonance (SPR) and cellular thermal shift assay (CETSA). addition, molecular docking showed could bind pocket form interactions residues. Further experiments revealed effectively inhibit migration epithelial-mesenchymal-transition (EMT) cells vitro vivo . These results reveal novel finding potential be agent inhibiting metastasis.
Language: Английский
Citations
11
Sexual Medicine, Journal Year: 2024, Volume and Issue: 12(6)
Published: Dec. 1, 2024
Language: Английский
Citations
1
International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(16), P. 9378 - 9378
Published: Aug. 19, 2022
Patients diagnosed with metastatic uveal melanoma (MUM) have a poor survival prognosis. Unfortunately for this rare disease, there is no known cure and suitable therapeutic options are limited. HDAC6 inhibitors (HDAC6i) currently in clinical trials other cancers show potential beneficial effects against tumor cell vitro vivo. In MUM cells, HDAC6i an anti-proliferative effect preclinical xenograft models. The use of as treatment option should be explored further. Therefore, review discusses (1) what about (2) whether offer MUM.
Language: Английский
Citations
4
PLoS ONE, Journal Year: 2023, Volume and Issue: 18(9), P. e0291779 - e0291779
Published: Sept. 18, 2023
Acetylation of lysine residues is an important and common post-translational regulatory mechanism occurring on thousands non-histone proteins. Lysine deacetylases (KDACs or HDACs) are a family enzymes responsible for removing acetylation. To identify the biological mechanisms regulated by individual KDACs, we created HT1080 cell lines containing chromosomal point mutations, which endogenously express either KDAC6 KDAC8 having single inactivated catalytic domain. Engineered cells expressing inactive KDA6 domains remained viable exhibited enhanced acetylation known substrate RNA-seq analysis revealed that many changes in gene expression were observed when KDACs inactivated, these sets differed significantly from knockdown knockout lines. Using GO ontology, identified several critical processes associated specifically with activity others attributable to non-catalytic interactions. Treatment wild-type KDAC-specific inhibitors Tubastatin A PCI-34051 resulted distinct those engineered lines, validating this approach as tool evaluating in-cell inhibitor specificity identifying off-target effects KDAC inhibitors. Probing functions specific using not equivalent doing so previously existing methods provides novel insight into investigating molecular cellular upon genetic inactivation.
Language: Английский
Citations
2
Biological and Pharmaceutical Bulletin, Journal Year: 2024, Volume and Issue: 47(10), P. 1734 - 1745
Published: Oct. 29, 2024
Spinal cord injury (SCI), a public health problem caused by mechanical injury, leads to secondary excessive inflammatory reactions and long-term damage neurological function. ACY1215 is highly selective histone deacetylase 6 (HDAC6) inhibitor reportedly has anti-inflammatory effects; however, its regulatory role in SCI not been studied. The purpose of this study was explore the preventing inflammation, inhibiting astrogliosis, enhancing remyelination preserving axons after spinal further exploring possible cellular signaling pathways involved. First, lipopolysaccharide (LPS) utilized stimulate rat astrocytes vitro. Quantitative RT (qRT)-PCR Western blotting showed that inhibited expression glial fibrillary acidic protein (GFAP), interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNFα) LPS-activated astrocytes. In addition, results could inhibit signal transduction pathway nuclear factor-κB (NF-κB) transducer activator transcription 3 (STAT3). vivo, exert effects cytokines, including IL-1β, IL-6, TNF-α. Moreover, repaired reducing formation scars promoting nerve recovery. summary, can NF-κB STAT3 astrocytes, reduce inflammation ameliorate SCI. Our provide novel strategy for treatment
Language: Английский
Citations
0
Korean Journal of Physiology and Pharmacology, Journal Year: 2023, Volume and Issue: 28(1), P. 83 - 91
Published: Dec. 29, 2023
Hypoxia-inducible factor-1 alpha (HIF-1α) is a transcription factor activated under hypoxic conditions, and it plays crucial role in cellular stress regulation. While HIF-1α activity essential normal tissues, its presence the tumor microenvironment represents significant risk as can induce angiogenesis confer resistance to anti-cancer drugs, thereby contributing poor prognoses. Typically, undergoes rapid degradation normoxic conditions
Language: Английский
Citations
1
Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: unknown
Published: Dec. 16, 2024
Acute liver injury is a severe and potentially life-threatening condition. Currently, there are no specific effective treatments available. HDAC6 has been identified as promising strategy for treating ALI by inhibiting necrosis inflammation. In this study, series of pyrazole derivatives were designed to specifically target HDAC6, among which compound
Language: Английский
Citations
0