A5089212888- Histone Deacetylase Inhibitors Research
- Protein Degradation and Inhibitors
- Epigenetics and DNA Methylation
- Peptidase Inhibition and Analysis
- Computational Drug Discovery Methods
- Cancer-related gene regulation
- Neuroscience and Neuropharmacology Research
- Parasites and Host Interactions
- Cholinesterase and Neurodegenerative Diseases
- Ubiquitin and proteasome pathways
- Synthesis and pharmacology of benzodiazepine derivatives
- Protein Structure and Dynamics
- RNA modifications and cancer
- Chemical Synthesis and Analysis
- Genetics and Neurodevelopmental Disorders
- Click Chemistry and Applications
- Pharmacological Receptor Mechanisms and Effects
- Receptor Mechanisms and Signaling
- PARP inhibition in cancer therapy
- Signaling Pathways in Disease
- Sirtuins and Resveratrol in Medicine
- Phenothiazines and Benzothiazines Synthesis and Activities
- Calcium signaling and nucleotide metabolism
- HIV/AIDS drug development and treatment
- Autophagy in Disease and Therapy
Martin Luther University Halle-Wittenberg
2016-2025
Stiftung des öffentlichen Rechts an der Martin-Luther-Universität Halle-Wittenberg
2024-2025
Wittenberg University
2025
Luther University
2022
University Hospital Münster
2020
Inserm
2016
Université Toulouse III - Paul Sabatier
2016
Institut des Maladies Métaboliques et Cardiovasculaires
2016
Friedrich Schiller University Jena
2010-2012
Here we report the development of a proteolysis targeting chimera (PROTAC) based on combination unique features sirtuin rearranging ligands (SirReals) as highly potent and isotype-selective Sirt2 inhibitors with thalidomide, bona fide cereblon ligand. For first time, formation PROTAC by Cu(I)-catalyzed cycloaddition thalidomide-derived azide to an alkynylated inhibitor. This well versatile linking strategy can be readily adapted other targets. In HeLa cells, our SirReal-based induced...
Schistosomiasis is a major neglected parasitic disease that affects more than 265 million people worldwide and for which the control strategy consists of mass treatment with only available drug, praziquantel. In this study, series new benzohydroxamates were prepared as potent inhibitors Schistosoma mansoni histone deacetylase 8 (smHDAC8). Crystallographic analysis provided insights into inhibition mode smHDAC8 activity by these 3-amidobenzohydroxamates. The newly designed evaluated in...
Metal-dependent histone deacetylases (HDACs) are key epigenetic regulators that represent promising therapeutic targets for the treatment of numerous human diseases. Yet currently FDA-approved HDAC inhibitors nonspecifically target at least several 11 structurally similar but functionally different isozymes, which hampers their broad usage in clinical settings. Selective targeting single isozymes being developed, precise understanding molecular terms selectivity remains sparse. Here, we show...
The phenothiazine system was identified as a favorable cap group for potent and selective histone deacetylase 6 (HDAC6) inhibitors. Here, we report the preparation systematic variation of phenothiazines their analogues containing benzhydroxamic acid moiety zinc-binding group. We evaluated ability to selectively inhibit HDAC6 by recombinant HDAC enzyme assay, determining protein acetylation levels in cells western blotting (tubulin vs acetylation), assessing effects on various cancer cell...
Cytokines and chemokines are produced secreted by a broad range of immune cells including macrophages. Remarkably, little is known about how these inflammatory mediators released from the various cells. Here, endolysosomal cation channel TRPML2 shown to play direct role in chemokine trafficking secretion murine To demonstrate acute involvement processes, first isoform-selective agonist was generated, ML2-SA1. ML2-SA1 not only found directly stimulate release CCL2 macrophages but also...
HDAC11 is a class IV histone deacylase with no crystal structure reported so far. The catalytic domain of shares low sequence identity other HDAC isoforms, which makes conventional homology modeling less reliable. AlphaFold machine learning approach that can predict the 3D proteins high accuracy even in absence similar structures. However, fact models are predicted small molecules and ions/cofactors complicates their utilization for drug design. Previously, we optimized an model by adding...
Histone deacetylases (HDACs) are important modulators of epigenetic gene regulation and additionally control the activity non-histone protein substrates. While for HDACs 1–3 6 many potent selective inhibitors have been obtained, other subtypes much less is known on consequences their inhibition. The present report describes development substituted benzhydroxamic acids as HDAC8 inhibitors. Docking studies using available crystal structures used structure-based optimization this series...
Sirtuins are NAD+-dependent protein lysine deacylases implicated in aging-related diseases. Mammalian Sirtuin 4 (Sirt4) is located mitochondria and a potential therapeutic target for cancer metabolic diseases, but no potent selective Sirt4 inhibitors have been reported. Here, we describe the identification of Sirt4-specific small-molecule inhibitors. Testing hits from target-based virtual screen revealed 12 active compounds. A focused based on two top compounds, followed by...
Class I histone deacetylases (HDACs) are key regulators of cell proliferation and they frequently dysregulated in cancer cells. We report here the synthesis a novel series class-I selective HDAC inhibitors (HDACi) containing 2-aminobenzamide moiety as zinc-binding group connected with central (piperazin-1-yl)pyrazine or (piperazin-1-yl)pyrimidine moiety. Some compounds were additionally substituted an aromatic capping group. Compounds tested vitro against human HDAC1, 2, 3, 8 enzymes...
HDAC11 is a class IV histone deacylase with no crystal structure reported so far. The catalytic domain of shares low sequence identity other HDAC isoforms which makes the conventional homology modeling less reliable. AlphaFold neural network machine learning approach that can predict 3D proteins high accuracy even in absence similar structures. However fact models are predicted small molecules and ions/cofactors complicate their utilization for drug design. Previously we optimized an model...
A promising means in the search of new small molecules for treatment schistosomiasis (amongst other parasitic ailments) is by targeting epigenome. In present study, a docking based virtual screening procedure using crystal structure histone deacetylase 8 from Schistosoma mansoni (smHDAC8) was designed. From developed protocol, we were able to identify eight novel N-(2,5-dioxopyrrolidin-3-yl)-n-alkylhydroxamate derivatives as smHDAC8 inhibitors with IC50 values ranging 4.4–20.3 µM against...
In addition to involvement in epigenetic gene regulation, histone deacetylases (HDACs) regulate multiple cellular processes through mediating the activity of non-histone protein substrates. The knockdown HDAC8 isozyme is associated with inhibition cell proliferation and apoptosis enhancement several cancer lines. As shown studies, can be considered a potential target treatment forms such as childhood neuroblastoma. present work describes development proteolysis targeting chimeras (PROTACs)...
Histone deacetylases (HDACs) are epigenetic regulators and additionally control the activity of non-histone substrates. We recently demonstrated that inhibition HDAC8 overexpressed in various cancers reduces hepatocellular carcinoma tumorigenicity a T cell-dependent manner. Here, we present alkylated hydrazide-based class I HDAC inhibitors which n-hexyl side chain attached to hydrazide moiety shows selectivity vitro. Analysis mode most promising compound 7d against revealed...
Ethambutol (EMB) is a first-line anti-tuberculosis drug that also considered in treatment regimens for infections caused by non-tuberculous mycobacteria (NTM). EMB targets the arabinosyl transferases EmbCAB, which are important synthesis of cell wall constituents. To further explore and narrow down structural variability EMB, we synthesized three series new analogs. We tested their activity against Mycobacterium tuberculosis, smegmatis, abscessus intracellulare. Only analogs very closely...
<title>Abstract</title> Histone deacetylase (HDAC) inhibitors represent a newer class of anti-cancer agents that play key role in both epigenetic and non-epigenetic regulation, leading to cancer cell death, apoptosis, cycle arrest.. These are being tested numerous clinical trials against various diseases, including hematological solid malignancies. In the present study, we synthesized novel bicyclic hydroxamic acid derivatives them vitro I IIb HDACs investigate their inhibitory activity...
Proteolysis targeting chimeras (PROTACs) have proven to be a novel approach for the degradation of disease-causing proteins in drug discovery. One E3 ligases which efficient PROTACs been described is Von-Hippel-Lindau factor (VHL). However, development has so far often relied on minimum computational tools, that it mostly based trial-and-error process. Therefore, there great need resource- and time-efficient structure-based or approaches streamline PROTAC design. In this study, we present...