Cluster Drug & Target Discovery
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.
Welcome to the cluster Drug & Target Discovery, which combines the divisions of Toxicology (Prof. Van de Water) and Medicinal Chemistry (Prof. IJzerman).
In this cluster, we focus on advanced imaging-based phenotypic screening for drug target and drug lead discovery. As an example we study cancer metastasis and therapy resistance, for which we use RNA interference coupled to quantitative microscopy and quantitative systems biology modelling (see box below).
A second example is where we exploit cheminformatics to identify novel molecules with optimal target binding kinetics, affinity and selectivity. Such probes are vital for the understanding of pharmacological modulation of drug targets at the molecular level, which in turn can account for population variation at the protein level and thus impact precision medicine approaches.
In the end all our efforts are geared towards optimizing the desired therapeutic effect and minimizing adverse reactions of the drugs of tomorrow.
Cancer is a leading cause of death predominantly due to the drug resistant phenotype of metastatic cells. The aim of the cluster is to understand the signaling wiring in the metastatic cancer cells that drives cancer progression. With such understanding, metastatic cancer cells could be targeted by effective therapy. Our main emphasis is on the two most important drug targets in cancer, i.e. kinases and G protein-coupled receptors (GPCRs). These targets are highly “druggable”, which we exploit and further expand on in our drug discovery efforts.
Research Themes and principal investigators:
Drug Safety Sciences
This theme generally follows four approaches: High throughput microscopy, next generation human IPSC-derived reporter systems, Integrated omics approaches, and mathematical modelling of adverse outcome pathways.
We construct models at different biological scales: either we focus at the level of individual cells and their interactions (e.g., between immune cells and tumour cells) or at the intracellular level and molecular interactions.
Cancer Drug Target Discovery
Four approaches are followed in this theme:Unraveling cancer drug resistance mechanisms. Discovery of metastasis promoting candidate drug targets. Cell adhesion signaling: dynamics, migration, and metastasis, and mathematical modelling of cancer progression-related processes.
Better ligands for G Protein-Coupled Receptors
We have set ourselves the goal of synthesizing tailored compounds for the drug targets in our research programs, along four lines depending on the target's'need': Affinity Selectivity Binding kinetics Allosterism
Novel Receptor Concepts
G protein-coupled receptors (GPCRs) constitute an important protein family of drug targets.Recent findings, now point to novel concepts of drug action, and we are very interested in such novel concepts and their relevance for adenosine and other receptors.
Chem- and Bioinformatics of Drug Targets
While a diverse array of computational methods have been created, in our group we focus mostly on two key research areas: structure based methods (molecular modeling) and leveraging diverse and large-scale public data ('big data': cheminformatics, bioinformatics, and data mining).