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  • ||||||||||  praziquantel / Generic mfg.
    Novel, potent, and selective inhibitors of SmHDAC8 with schistosomicidal activity (Hall F-H (Indiana Convention Center)) -  Feb 14, 2023 - Abstract #ACSSp2023ACS_SP_12259;    
    There is no vaccine available and current treatment consists of Praziquantel monotherapy which is refractory to juvenile worms necessitating the need for new drug discovery...We have designed and synthesized 1,2,3,4-tetrahydroisoquinoline hydroxamic acids with low micromolar potency in vitro and isoform selectivity to HDAC8. We hypothesize the activity is due to a chemotype-induced conformational change unique to the HDAC8 isoform.
  • ||||||||||  Preclinical, Journal:  Postmenopausal osteoporosis: Effect of moderate-intensity treadmill exercise on bone proteomics in ovariectomized rats. (Pubmed Central) -  Jan 24, 2023   
    The protein-protein interaction network identified the key proteins, and the correlation analysis of these proteins and the bone parameters found histone deacetylase 8(HDAC8) and leucine-rich transmembrane and O-methyltransferase domain containing (LRTOMT) and trimethylguanosine synthase 1(TGS1) and ankyrin repeat domain 46(ANKRD46) to be the key targets of exercise in relation to postmenopausal osteoporosis. Moderate-intensity treadmill exercise significantly improved the bone mass of OVX rats, and differentially expressed proteins, such as HDAC8 and LRTOMT and TGS1 and ANKRD46, could be the target of moderate-intensity treadmill exercise.
  • ||||||||||  Zolinza (vorinostat) / Merck (MSD)
    Preclinical, Journal:  Therapeutic Efficacy of Novel HDAC Inhibitors SPA3052 and SPA3074 against Intestinal Inflammation in a Murine Model of Colitis. (Pubmed Central) -  Dec 24, 2022   
    Male C57BL/6N mice were subjected to two cycles of 1.5% DSS followed by treatment with suberoylanilide hydroxamic acid (SAHA), SPA3052, or SPA3074 for 14 days...Th2 effector cytokines, especially interleukin-13, were also downregulated by SPA3074 treatment. This study suggests that HDAC8 might be a promising novel target for the development of IBD treatments and that the novel HDAC8 inhibitor SPA3074 is a new candidate for IBD therapeutics.
  • ||||||||||  doxorubicin hydrochloride / Generic mfg.
    Journal:  Dual LSD1 and HDAC6 Inhibition Induces Doxorubicin Sensitivity in Acute Myeloid Leukemia Cells. (Pubmed Central) -  Dec 12, 2022   
    Remarkably, iDual synergized with doxorubicin, triggering significant levels of apoptosis with a sublethal concentration of the drug. While mechanistic studies did not reveal changes in DNA repair or drug efflux pathways, the expression of AGPAT9, ALOX5, BTG1, HIPK2, IFI44L, and LRP1, previously implicated in doxorubicin sensitivity, was significantly elevated.
  • ||||||||||  trichostatin A (VTR-297) / Vanda
    Journal:  Screening for eukaryotic motifs in Legionella pneumophila reveals Smh1 as bacterial deacetylase of host histones. (Pubmed Central) -  Nov 23, 2022   
    Furthermore, Smh1 showed a very potent histone deacetylation activity in vitro, e.g. at H3K14, that could be inhibited by targeted mutation of the putative catalytic centre inferred by analogy with eukaryotic HDAC8, and with the deacetylase inhibitor trichostatin A. In summary, Smh1 displays functional homology with class I/II type HDACs. We identified Smh1 as a new Legionella virulence factor with a eukaryote-like histone-deacetylase activity that moderates host gene expression and might pave the way for further histone modifications.
  • ||||||||||  Zolinza (vorinostat) / Merck (MSD), entinostat (SNDX-275) / Syndax Pharma, EOC Pharma
    Journal, Epigenetic controller:  Synthesis, antitumor, and apoptosis-inducing activities of novel 5-arylidenethiazolidine-2,4-dione derivatives: Histone deacetylases inhibitory activity and molecular docking study. (Pubmed Central) -  Nov 22, 2022   
    The antitumor activity of the newly synthesized 5-arylidenethiazolidine-2,4-dione derivatives 18a-f and 19a-f was investigated, compared to doxorubicin (IC = 4.17-8.87 μM) and SAHA (IC = 2.70-7.11 μM)...Further, compounds 18b, 18c, 18f, and 19d were tested as Histone deacetylases (HDACs) inhibitors compared with Entinostat (IC = 0.093-0.75 μM)...It also increased caspases-3 and caspases-7 by 5.2-3.9 and 9.1-3.7 folds, respectively. The molecular docking analysis of compounds 18b and 18c revealed that they could bind to the active sites of HDAC1, HDAC2, HDAC8, and HDAC6 like co-crystallized inhibitors.
  • ||||||||||  Journal:  Rational design of metabolically stable HDAC inhibitors: An overhaul of trifluoromethyl ketones. (Pubmed Central) -  Nov 22, 2022   
    Some of the most active analogues inhibited HDAC enzymes with low nanomolar IC values and were found to be more selective for HDAC8 over other isoforms. These molecules provide a new class of HDAC inhibitors with a metabolically stable metal-binding group that could be used to develop selective HDAC inhibitors by further structural modification.
  • ||||||||||  Journal:  3-Chloro-5-substituted-1,2,4-thiadiazoles (TDZs) as selective and efficient protein thiol modifiers. (Pubmed Central) -  Nov 9, 2022   
    And at the example of human HDAC8 we demonstrate that cysteine modification by a 5-sulfonyl-TDZ can be readily applied in commonly used biotin switch assays. And at the example of human HDAC8 we demonstrate that cysteine modification by a 5-sulfonyl-TDZ is easily measurable using quantitative HPLC/ESI-QTOF-MS/MS, and even allows for the simultaneous measurement of the modification kinetics of seven solvent accessible cysteines in HDAC8.
  • ||||||||||  HDAC8 Disrupts DNA Damage Response By Deacetylation of U2AF1 in Inv(16) Acute Myeloid Leukemia (ENMCC - Hall D) -  Nov 4, 2022 - Abstract #ASH2022ASH_5711;    
    Collectively, our results suggest that the increased DNA damage induced by CM may be due to the reduced acetylation of U2AF1 resulting from high HDAC8 activity. These results highlight a direct impact of inv(16) fusion protein and high HDAC8 activity on increased genomic instability in AML.
  • ||||||||||  Journal, Epigenetic controller:  Crystal structures of Schistosoma mansoni histone deacetylase 8 reveal a novel binding site for allosteric inhibitors. (Pubmed Central) -  Nov 3, 2022   
    We determined that by acting on this site, either by mutation of the Trp198 or by compound binding, a decrease in the activity of the enzyme is achieved. Remarkably, this allosteric site differs from the human counterpart; rather, it is conserved in all Schistosoma spp., as well as Rhabidoptera and Trematoda classes, thus paving the way for the design of HDAC8-selective allosteric inhibitors with improved properties.
  • ||||||||||  A Novel Brain Permeable Epigenetic Inhibitor Ameliorates Neuropathic Pain in Mouse (Grand Saguaro) -  Oct 31, 2022 - Abstract #ACNP2022ACNP_593;    
    Since HDACs have been implicated in neurologic pain, we further determined whether PB94 treatment could ameliorate neurologic pain using the CCI mice model. The unilateral sciatic nerve chronic constriction injury surgery is associated with postoperative spontaneous pain, mechanical allodynia, and thermal hyperalgesia.
  • ||||||||||  Journal:  Development of a Cellular Model Mimicking Specific HDAC Inhibitors. (Pubmed Central) -  Oct 25, 2022   
    We here describe the generation of a genetic toolbox by the CRISPR/Cas9 methodology in nearly haploid human tumor cells. This novel model system allows to discriminate between catalytic and structural functions of class I HDAC enzymes and to mimic the treatment with specific HDAC inhibitors.
  • ||||||||||  Review, Journal:  Pathological Role of HDAC8: Cancer and Beyond. (Pubmed Central) -  Oct 22, 2022   
    Therefore, HDAC8 is an attractive therapeutic target and various HDAC8 selective inhibitors (HDAC8is) have been developed. Here, we address the pathological function of HDAC8 in cancer and other diseases, as well as illustrate several HDAC8is that have shown anti-cancer effects.
  • ||||||||||  Journal:  Chemically Diverse S. mansoni HDAC8 Inhibitors Reduced Viability in Worm Larval and Adult Stages. (Pubmed Central) -  Oct 18, 2022   
    Such compounds were tested against schistosomula, and a selection of them against the adult forms of S. mansoni, to detect their effect on viability. Some of them showed the highest viability reduction for the larval stage with IC50 values around 1 µM and/or displayed ~ 40-50% activity in adult worms at 10 µM, joined to moderate to no toxicity in human fibroblast MRC-5 cells.
  • ||||||||||  Journal:  HDAC8 is implicated in embryoid body formation via canonical Hedgehog signaling and regulates neuronal differentiation. (Pubmed Central) -  Oct 5, 2022   
    We found that HDAC8 is possibly involved in regulating the expression of the Smoothened receptor (Smo), an important receptor in canonical Hh signaling, and treatment with a Smo agonist restored EB formation ability, which was reduced in HDAC8 knockout P19EC cells. Our results demonstrate that HDAC8 functions in EB formation, which is involved in the Hh signaling pathway that is important for embryonic development.
  • ||||||||||  praziquantel / Generic mfg.
    Journal, Epigenetic controller:  Phenotypic Screening of Histone Deacetylase (HDAC) Inhibitors against Schistosoma mansoni. (Pubmed Central) -  Sep 29, 2022   
    Praziquantel is the only currently available treatment, hence drug resistance poses a major threat...Pan-HDAC inhibitors MMH258, MMH259, and MMH373, as assessed by functional inhibition assays, with minimal or no-observed hHDAC8 and SmHDAC8 activities, were active against both NTS (MMH258, IC =1.5 μM; MMH259, IC =2.3 μM) and adult S. mansoni (MMH258, IC =2.1 μM; MMH373, IC =3.4 μM). Our results indicate that neither hHDAC8 nor SmHDAC8 activity were directly correlated to their NTS and adult S. mansoni activities.
  • ||||||||||  Journal, Epigenetic controller:  Histone Deacetylases Cooperate with NF-κB to Support the Immediate Migratory Response after Zebrafish Pronephros Injury. (Pubmed Central) -  Sep 18, 2022   
    Furthermore, time-lapse video microscopy revealed that the lamellipodia and filopodia formation in the flanking cells was strongly reduced in hdac6-depleted embryos. Our findings suggest that Hdac activity and NF-κB are synergistically required for the immediate repair response in the zebrafish pronephros model of AKI, and the timing of HDAC inhibition might be important in developing supportive protocols in the human disease.
  • ||||||||||  Review, Journal:  A Therapeutic Perspective of HDAC8 in Different Diseases: An Overview of Selective Inhibitors. (Pubmed Central) -  Sep 18, 2022   
    In this frame, proteolysis-targeting chimeras (PROTACs) might be regarded as a dual-targeting approach for attaining HDAC8 proteasomal degradation. This review highlights the most relevant and recent advances relative to HDAC8 validation in various diseases, providing a snapshot of the current selective HDAC8is, with a focus on polyfunctional modulators.
  • ||||||||||  Journal:  A Novel Intragenic Duplication in the HDAC8 Gene Underlying a Case of Cornelia de Lange Syndrome. (Pubmed Central) -  Sep 3, 2022   
    The aberrant transcript was predicted to generate a truncated protein whose accessibility to the active center was restricted, showing reduced ease of substrate entry into the mutated enzyme. Lastly, we conclude that the duplication is responsible for the patient's phenotype, highlighting the contribution of CNVs as a molecular cause underlying CdLS.
  • ||||||||||  CRA-026440 / Quest Diagnostics, citarinostat (ACY-241) / BMS
    Journal:  HDAC8-Selective Inhibition by PCI-34051 Enhances the Anticancer Effects of ACY-241 in Ovarian Cancer Cells. (Pubmed Central) -  Aug 22, 2022   
    Overall, co-inhibition of HDAC6 and HDAC8 through selective inhibitors synergistically suppresses cancer cell proliferation and metastasis in p53 wild-type ovarian cancer cells. These results suggest a novel approach to treating ovarian cancer patients and the therapeutic potential in developing HDAC6/8 dual inhibitors.
  • ||||||||||  Investigating the role of histone deacetylases in human epidermis () -  Aug 16, 2022 - Abstract #ESDR2022ESDR_403;    
    Taken together, these data suggest that HDAC activity significantly changes throughout the life course. Further studies exploring these changes are warranted at both the transcriptional and translational level using primary keratinocytes to better understand the role of epigenetic tuning in keratinocyte differentiation and ageing.
  • ||||||||||  Journal:  Synthesis and HDAC inhibitory activity of pyrimidine-based hydroxamic acids. (Pubmed Central) -  Aug 6, 2022   
    The synthesized hydroxamic acids were tested as inhibitors of the HDAC4 and HDAC8 isoforms. Among the synthesized pyrimidine-based hydroxamic acids N-hydroxy-6-[6-methyl-2-(methylthio)-5-propylpyrimidin-4-yloxy]hexanamide was found to be the most potent inhibitor of both the HDAC4 and HDAC8 isoforms, with an IC of 16.6 µM and 1.2 µM, respectively.