208 search results for “kinase inhibitors” in the Public 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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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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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 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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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 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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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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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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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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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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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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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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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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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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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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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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Key publications
Key publications of the Computational Drug Discovery group
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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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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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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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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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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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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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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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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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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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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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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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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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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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Tong ZhaoScience
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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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Key publications
Key publications of the Quantitative Pharmacology group
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Modulating the behaviour of pancreatic tumour cells
Promotores: Prof.dr. M.K. Richardson, Prof.dr. H.P. Spaink