192 search results for “parp inhibitors” in the Public website
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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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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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Resistance to PARP inhibition by DNA damage response alterations in BRCA1/2-deficient tumors
Inactivating mutations in BRCA1 or BRCA2 genes predispose to several types of cancer.
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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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Discovery of BUB1 kinase inhibitors for the treatment of cancer
The spindle-assembly checkpoint (SAC) is a safety mechanism which secures accurate chromosome segregation during mitosis.
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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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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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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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Cancer Chess: Molecular Insights into PARP Inhibitor Resistance
PhD defence
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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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Exploring chemical space in covalent and competitive glycosidase inhibitor design
Glycoside hydrolases (glycosidases/GHs) are widely abundant enzymes in all kingdoms of life and are important biocatalysts that catalyze the hydrolysis of glycosidic linkages in oligo/polysaccharides, glycoproteins and glycolipids with tremendous efficiency
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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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Using functional genetic screens to understand and overcome PARP inhibitor resistance
PhD defence
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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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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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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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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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Division of Drug Discovery & Safety
We are interested in the efficacy and safety of new drugs and novel means to decipher these aspects. Hence, we employ advanced imaging and high-throughput screening techniques next to computational approaches such as chem- and bioinformatics.
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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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Synthetic Methodology Towards ADP-Ribosylation Related Molecular Tools
Phosphorylation affects all four major biomolecules – proteins, lipids, carbohydrates and nucleic acids – and plays a pivotal role in the most fundamental cellular functions.
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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 CodeeScience
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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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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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Madouc Bergers made her own enzyme inhibitors for her bachelor’s thesis
For her bachelor’s thesis, Molecular Science and Technology student Madouc Bergers synthesized her own molecule that can inhibit the breakdown of sugars. Although most students do not even manage to make one building block, Madouc made three. Partly because of this, she has been nominated for the Science…
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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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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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Hermen OverkleeftScience
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Elmer MauritsScience
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Tom van der WelScience
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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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Immune checkpoint inhibitors in mesothelioma
PhD defence
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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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Resistance to PARP inhibition by DNA damage response alterations in BRCA1/2-deficient tumors
PhD defence