233 search results for “kinase inhibitor” in the Public website
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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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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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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 AGC3 kinases and calmodulins in plant growth responses to abiotic signals
Promotor: Prof.dr. P. Hooykaas, Co-promotor: Dr. R. Offringa
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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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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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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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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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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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Determining the kinetic profile of ENT1 inhibitors
Supervisor: Anna Vlachodimou
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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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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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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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Development of kinase inhibitors and activity based probes
PhD Defence
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Key publications
Key publications of the Computational Drug Discovery group
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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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Determining the structure of a chemotaxis kinase complex with receptor mimetics and cryo-EM
Can we determine the 3D structure of a chemotaxis core complex using single-particle reconstructions via cryo-EM?
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Chemical genetics strategy to profile kinase target engagement reveals role of FES in neutrophil phagocytosis, Nat. Comm. 2020
Chemical tools to monitor drug-target engagement of endogenously expressed protein kinases are highly desirable for preclinical target validation in drug discovery. Here, we describe a chemical genetics strategy to selectively study target engagement of endogenous kinases.
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Tom van der WelScience
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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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Research
The current projects of the Molecular Physiology group focus on proteins of the endocannabinoid system, kinases and antibacterial targets. MSc- and BSc-students can contact Jessica van Krimpen-Kraaijenoord to apply for research internships.
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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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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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Covalent inhibitors of G protein-coupled receptors: the case of adenosine receptors
Supervisor: Xue Yang
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Student projects
Bachelor and Master students of all chemistry related studies are more than welcome to take part in our research activities. We have projects on design and synthesis of biologically relevant compounds within an ongoing research project. Supervision, following the apprentice/teacher model, is one of…
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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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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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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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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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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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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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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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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 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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Mario van der SteltScience
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Modulating the behaviour of pancreatic tumour cells
Promotores: Prof.dr. M.K. Richardson, Prof.dr. H.P. Spaink
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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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Key publications
Key publications of the Quantitative Pharmacology group
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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