225 search results for “irreversible inhibitors” in the Public website
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Discovery of Reversible Monoacylglycerol Lipase Inhibitors
Monoacylglycerol lipase (MAGL) is the principal enzyme responsible for hydrolysis of the endocannabinoid 2-arachidonoylglycerol (2-AG). MAGL inhibition provides several potential therapeutic opportunities, including anti-nociceptive, anti-inflammatory and anti-cancer activity.
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Inhibitor discovery of phospholipases and N-acyltransferases
In this thesis an activity-based probe was discovered that could visualize the activity of PLAATs. With an optimized gel-based ABPP assay in hand, screening of a compound library led to the discovery of alpha-ketoamides as a hit for PLAAT3.
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Small molecule inhibitors of Nicotinamide N-Methyltransferase (NNMT)
NNMT wordt beschouwd als een nieuw potentieel farmacologisch doelwit in de behandeling van een verscheidenheid van kankers, stofwisselingsziekten en andere pathologieën. Het toenemend aantal publicaties waarin de rol van NNMT bij ziekten wordt opgehelderd, heeft op zijn beurt de ontwikkeling van krachtige…
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Targeting Human Proteasomes: Substrates, Inhibitors and Prodrugs
Large parts of the research described in this Thesis aims at the development of oligopeptide-masked toxins and their in situ immunoproteasome-mediated activation.
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Inhibitor Selectivity: Profiling and Prediction
Less than 1 in 10 drug candidates that enter phase 1 clinical trials actually gets approved for human use.
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Development of kinase inhibitors and activity-based probes
Promotor: H.S. Overkleeft, J. Neefjes, Co-promotor: M. van der Stelt
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Small-molecule inhibitors of bacterial metallo-β-lactamases
The main focus of the thesis is the discovery and development of novel inhibitors of bacterial metallo-β-lactamases (MBLs).
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Inhibitors and probes targeting endo-glycosidases
The chemical synthesis of inhibitors and probes targeting endo-glycosidases.
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Determining the kinetic profile of ENT1 inhibitors
Supervisor: Anna Vlachodimou
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Discovery of FLT3 inhibitors for the treatment of acute myeloid leukemia
The disease acute myeloid leukemia (AML) is characterized by fast progression and low survival rates.
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and its derivatives: synthesis and application as beta-glycosidase inhibitors
Promotores: Prof.dr. H.S. Overkleeft, Prof.dr. G.A. van der Marel
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Cancer chess: molecular insights into PARP inhibitor resistance
The clinical potential of applying synthetic lethality to cancer treatment is famously demonstrated by the BRCA1/PARP1 paradigm: a tumor specific defect in BRCA1 – a component of the DNA double-strand break (DSB) repair pathway homologous recombination (HR) – results in a remarkable sensitivity to PARP1…
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Direct and two-step activity-based profiling of proteases and glycosidases
Promotores: Prof.dr. H.S. Overkleeft, Prof.dr. G.A. van der Marel
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Iminosugars as glucosylceramide processing enzymes inhibitors: design, synthesis and evaluation
This Thesis describes the design, synthesis and evaluation as glycoprocessing enzyme inhibitors of focused libraries of iminosugars.
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The synthesis of mannose-derived bioconjugates and enzyme inhibitors
Promotores: H.S. Overkleeft, G.A. van der Marel, Co-Promotor: J.D.C. Codee
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Fluorescence Polarization Activity-Based Protein Profiling on Retaining Glycosidases
Glycosidases are important enzymes in the turnover of polysaccharides and glycoconjugates, and are involved in a range of human pathologies including genetic disorders such as Gaucher and Pompe disease, but also in various cancers.
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Understanding functional dynamics and conformational stability of beta-glycosidases
Due to their central physiological roles in living organisms, retaining beta-glycosidases have been the subject of tremendous research efforts to examine their structure/function relation using numerous biophysical and biochemical approaches.
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Discovery of novel inhibitors to investigate diacylglycerol lipases and α/β hydrolase domain 16A
Promotor: H.S. Overkleeft, Co-promotor: M. van der Stelt
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Discovery and development of inhibitors selective for human constitutive proteasome and immunoproteasome active sites
This thesis describes the design and development of subunit‐selective inhibitors of particular catalytically active subunits of human constitutive proteasomes and immunoproteasomes.
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Prediction of the potency of mammalian cyclooxygenase inhibitors with ensemble proteochemometric modeling
Source: J Cheminform, Volume 7, Issue 1 (2015)
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Design and development of conformational inhibitors and activity-based probes for retaining glycosidases
Glycosidases are essential in fundamental biological processes and are responsible for the degradation of most (oligo)saccharides, glycolipids and glycoproteins.
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Relative quantification of proteasome activity by activity-based protein profiling and LC-MS/MS
Activity-based protein profiling (ABPP) is a functional proteomics technique for directly monitoring the expression of active enzymes in cell extracts and living cells. The technique relies on irreversible inhibitors equipped with reactive groups (warheads) that covalently attach to the active site…
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Mycobacterial dihydrofolate reductase inhibitors identified using chemogenomic methods and in vitro validation
Source: PLoS ONE, Volume 10, Issue 3 (2015)
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Covalent inhibitors of G protein-coupled receptors: the case of adenosine receptors
Supervisor: Xue Yang
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Discovery of a NAPE-PLD inhibitor that modulates emotional behavior in mice, Nat. Chem. Biol. 2020
N-acylethanolamines (NAEs), which include the endocannabinoid anandamide, represent an important family of signaling lipids in the brain. The lack of chemical probes that modulate NAE biosynthesis in living systems hamper the understanding of the biological role of these lipids.
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solution and crystallographic studies of the Sso10a2 and human C1 inhibitor protein
Promotor: J.P. Abrahams, Co-Promotor: N.S. Pannu
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candidate || Identification and characterization of small molecule inhibitors of type VII protein secretion systems (1.0 fte)
Science, Leiden Institute of Chemistry (LIC)
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Activity-based protein profiling reveals off-target proteins of the FAAH inhibitor BIA 10-2474, SCIENCE, 2017
The drug BIA 10-2474 inhibits fatty acid amide hydrolase (FAAH), a lipase that degrades a specific endocannabinoid. On the basis of this activity, BIA 10-2474 was being developed as a potential treatment for anxiety and pain. In a phase 1 trial of the drug, one subject died, and four others suffered…
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insight from a binding kinetics study of prototypical Kv 11.1 (hERG) inhibitors
Source: Br. J. Pharmacol., Volume 172, Issue 3, pp. 940-55 (2015)
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PhD candidate || Identification and characterization of inhibitors of carbohydrate modifying enzymes to generate a new type of anti-bacterial
Science, Leiden Institute of Chemistry (LIC)
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PhD student, to identify and characterize inhibitors of carbohydrate modifying enzymes to generate a new type of anti-viral molecule
Science, Leiden Institute of Chemistry (LIC)
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Targeted Therapy for Triple-Negative Breast Cancer
The research described in this thesis focused on identifying novel drug targets and synergistic combinations for triple-negative breast cancer (TNBC), a virulent subtype of breast cancer with a dismal prognosis and limited therapeutic options.
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Research
Research at the BIOSYN group is comprised of the following research themes:
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Cyclophellitol analogues for profiling of exo- and endo-glycosidases
To this day, all cyclophellitol-based inhibitors and ABPs have been close analogues of their natural substrate counterparts. As a result, these probes showed high selectivity towards their target glycosidases.
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Jeroen Codee
Science
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Osteosarcoma: searching for new treatment options
Promotores: B. van de Water; P. Hogendoorn; J. Bovée Co-Promotor: E.H.J. Danen
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Fundamental Research in Chemical Biology
Chemical biology research at the Leiden Institute of Chemistry is aimed at understanding biological processes at the molecular level to strengthen the knowledge base of human health and disease. The approach to achieve this goal is a fundamental chemical one; with the aid of chemical probes biological…
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Chemical Biology
Chemical biology research at the Leiden Institute of Chemistry is aimed at understanding biological processes at the molecular level to strengthen the knowledge base of human health and disease. The approach to achieve this goal is a fundamental chemical one; with the aid of chemical probes biological…
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Chemical tools to monitor and control human proteasome activities
Promotores: H.S. Overkleeft; G.A. van der Marel Co-Promotor: B.I. Florea
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How Electrostatic Interactions Drive Nucleosome Binding of RNF168 & PSIP1
The studies presented in the work show the potential of the integrative use of biophysical data in defining the structural basis of protein interactions.
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Elmer Maurits
Science
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Hermen Overkleeft
Science
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Choice-related stress and uncertainty
What are the behavioral, cognitive, and motivational consequences of decision reversibility?
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Tom van der Wel
Science
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Anthe Janssen wins the YMCS Public's Choice Prize
Anthe Janssen, a PhD student in the Molecular Physiology research group of Prof. Mario van der Stelt, has been awarded the Public's Choice Prize for Best Oral Presentation during the Young Medicinal Chemist Symposium '18 in Ljubljana, Slovenia.
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Activity-based protein profiling of diacylglycerol lipases
Promotor: H.S. Overkleeft, Co-promotor: M. van der Stelt
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Inhibitor Selectivity: Profiling and Prediction
PhD Defence
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Precision modeling of breast cancer in the CRISPR era
The molecular mechanisms that instigate a healthy cell to become malignant are fueled by (epi)genetic alterations in so-called driver genes.
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Illuminating N-acylethanolamine biosynthesis with new chemical tools
In this thesis, the discovery and optimization is described of chemical tools to study the N-acylethanolamine (NAE) biosynthetic pathway.
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Structural characterization of bacterial proteins involved in antibiotic resistance and peptidoglycan biosynthesis
This thesis describes the structural and biochemical characterization of the β-lactamase BlaC from Mycobacterium tuberculosis (Mtb), and the Alr and YlmE proteins from Streptomyces coelicolor A3(2).Mtb is the main cause of tuberculosis.