120 zoekresultaten voor “kinase inhibitor” in de Publieke website
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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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Development of kinase inhibitors and activity-based probes
Promotor: H.S. Overkleeft, J. Neefjes, Co-promotor: M. van der Stelt
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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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CellEKT: a chemical proteomics platform to study the kinome
Kinase inhibitors are key therapeutic agents, particularly in oncology, yet their clinical efficacy is often hampered by off-target effects and limited understanding of their cellular target profiles.
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High-throughput screening using fluorescent cell models for mechanistic evaluation of adverse drug reactions
This thesis aims to test in vitro pipelines to rapidly and cost-effectively identify molecular mechanisms that drive adverse outcomes in clinical use.
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Arabidopsis AGC3 kinases and PIN plasma membrane abundance
The plant hormone auxin plays a central role in the growth and development of plants. Auxin acts in a concentration dependent manner and polar cell-to-cell transport of this hormone determines its distribution in the tissues of plants. This polar auxin transport is mediated by several families of auxin…
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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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Disrupting the transcriptional machinery to combat triple-negative breast cancer
Triple-negative breast cancer (TNBC) is a subtype of breast cancer characterized by limited treatment options and unfavorable clinical outcomes. Therefore, the research described in this thesis focused on the exploration of novel targeted therapies for TNBC.
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Discovery of selective diacylglycerol lipase β inhibitors
Diacylglycerol lipases (DAGLα and DAGLβ) are responsible for the biosynthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG) in the brain and peripheral tissues. Selective DAGLβ inhibitors have been proposed as a potential treatment for inflammatory diseases with reduced potential for central…
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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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The role of AGC kinases and auxin in male fertility
The thesis is about how auxin and AGC kinases regulate male fertility. The main AGC kinases studied in this thesis is PDK1, PDK2 and AGC1.5, AGC1.7.
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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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Inhibitors and probes targeting mannanases
This thesis describes the synthesis and biochemical evaluation of a variety of cyclophellitol based activity-based probes and inhibitors targeting various endo- and exo-acting retaining glycosidases. In the last two decades a variety of probes and inhibitors for (hemi)cellulose degrading enzymes have…
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Inhibitors and probes targeting PslG
Pseudomonas Aeruginosa is a Gram-negative bacterium which can form biofilms, increasing its resistance against antibiotics and the host immune system. Polysaccharides are an integral part of this biofilm, one of these polysaccharides is called Psl. PslG is a glycosidase, able to cleave this polysaccharide,…
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Substrates and inhibitors to study and modulate ER-I α-glucosidase activity
This thesis describes research aimed at discovering inhibitors selective for either of the two endoplasmic reticulum α-glucosidases, ER-I and ER-II, with the overarching goal of discovering new antiviral agents to treat viruses that rely on host N-glycosylation for proliferation.
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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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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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The role of AGC3 kinases and calmodulins in plant growth responses to abiotic signals
Promotor: Prof.dr. P. Hooykaas, Co-promotor: R. Offringa
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Inhibitors and activity-based probes for β-D-glucuronidases, heparanases and β-L-arabinofuranosidases
Glycosidases (GHs) are enzymes responsible for the degradation of carbohydrates and play many roles in human health and pathophysiology. Often, abnormal levels of glycosidase activity are markedly linked to human pathologies.
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Novel factors modulating AGC kinase signaling-controlled polar auxin transport
The PID-directed shift in PIN polarity has been broadly accepted as one of the essential mechanisms for the regulation of auxin transport polarity.
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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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Functions of P38 and ERK kinases in zebrafish early development
Promotor: Prof.dr. H.P. Spaink, Co-promotor: Dr. B.E. Snaar
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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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Evolutionary adaptability of β-lactamase: a study of inhibitor susceptibility in various model systems
β-Lactamases are enzymes that can break down β-lactam substrates, such as antibiotics, preventing the use of these antibiotics for the treatment of various infectious diseases. However, some compounds, β-lactamase inhibitors, can block these enzymes allowing for possible treatments using a combination…
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Regulation of the arabidopsis AGC kinase PINOID by PDK1 and the microtubule cytoskeleton
Plants, are sessile organisms, have developed strategies to adapt to changes in their environment, in part by altering their growth and development.
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Design and Synthesis of Inhibitors and Probes for Sulfoquinovosidases and Xylanases
This thesis focuses on the design and synthesis of activity-based probes and inhibitors targeting enzymes involved in the degradation of specific plant glycans.
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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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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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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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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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Design of selective inhibitors for human immunoproteasomes
The thesis describes the development, synthesis and biological evaluation of several proteasome inhibitor designs. Mainly, this work focusses on designing proteasome inhibitors that selectively inhibit the immunoproteasome, while leaving the constitutive proteasome mostly, if not completely, untouch…
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Inhibitors and probes targeting endo-glycosidases
The chemical synthesis of inhibitors and probes targeting endo-glycosidases.
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Chemical genetic approaches for target validation
Drug development is a time- and resource-consuming process that starts with the discovery and validation of a (protein) target that contributes to pathogenesis or disease progression.
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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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Mechanism-based inhibitors and probes for neuraminidases
Neuraminidases are enzymes that cleave glycosidic linkages of sialic acid. These enzymes are involved in influenza infections as well as in many cellular processes in mammals and micro-organisms.
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solution and crystallographic studies of the Sso10a2 and human C1 inhibitor protein
Promotor: Prof.dr. J.P. Abrahams, Co-Promotor: N.S. Pannu
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Uncovering vulnerabilities in triple-negative breast cancer
Triple-negative breast cancer (TNBC) constitutes a small subtype (~15%) of breast cancer, but causes the majority of breast cancer-related deaths.
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of branched swainsonines as selective Colgi alpha-mannosidase II inhibitors
Design and synthesis of two 3-substituted swainsonine derivatives with the aim to improve the potency and selectivity towards Golgi alpha-mannosidase II.
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Design and synthesis of next generation carbohydrate-mimetic cyclitols: towards deactivators of inverting glycosidases and glycosyl transferases
Synthetic methodlogy is described, aiding in the synthetic preparation of putative inhibitors of retaining and inverting glycosidases and glycosyl transferases. All constructs are cyclophellitol-based cyclitols.
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Mast cells in advanced atherosclerosis: from human plaque stability to new therapeutic targets
In this thesis, the role of mast cells in atherosclerosis and novel therapeutic strategies to inhibit atherosclerosis progression are discussed. The first part of the thesis specifically focuses on the relation between mast cells and advanced human atherosclerotic plaque characteristics.
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Evolvability and epistasis studied through the lens of an antibiotic resistance enzyme
Enzymes are innately sensitive to changes in the amino acid sequence, which largely constrains their evolutionary potential, i.e., evolvability. This evolutionary burden can be alleviated in the presence of stabilizing mutations, which increase the buffering capacity of enzymes to tolerate mutations…
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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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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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Unieke medicijnstructuren vinden met kunstmatige intelligentie en scheikunde
In de zoektocht naar nieuwe medicijnen tegen onder andere kanker heeft een Leids team een nieuwe werkwijze ontwikkeld. Dit stappenplan combineert kunstmatige intelligentie (AI) met moleculair modelleren en is geschikt om onbekende en vernieuwende medicijnstructuren te vinden, zo bewezen de onderzoek…
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To affinity and beyond: novel molecular tools to explore solute carrier transport proteins
Despite being the second largest transmembrane protein family after GPCRs, the SLC superfamily has only gained significant attention in early drug development over the past decade.
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Modulating the behaviour of pancreatic tumour cells
Promotores: Prof.dr. M.K. Richardson, Prof.dr. H.P. Spaink. Co-promotor: C.P. Bagowski
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Chemical tools to monitor and control proteasome activities
Promotores: H.S. Overkleeft; G.A. van der Marel Co-Promotor: B.I. Florea