A chemical biology and medicinal chemistry approach to discover drug candidates

Dr. Mario van der Stelt

In a multidisciplinary research line, in which organic and medicinal chemistry are combined with molecular biology and chemical biology, we aim to a) develop assays to determine the activity of proteins, and b) to design, synthesize and characterize small molecules that act as chemical tools to visualize and control protein activity. We use computational chemistry together with activity-based probes for compound profiling and optimization. In (inter)national collaborations with biologists and pharmacologists we test our molecules in preclinical models of disease. Our current projects focus on kinases and proteins of the endocannabinoid system.

Detection and modulation of endocannabinoid biosynthesis

Endocannabinoids are endogenous signalling lipids that activate cannabinoid CB1-receptors. Continuous stimulation of the CB1-receptor is associated with nicotine addiction, obesity and the metabolic syndrome (all major risk factors for illness and death in Europe). The CB1-receptor antagonist rimonabant was effective in obese patients, but withdrawn from the European market due to unacceptable psychiatric side effects. This highlights the medical need to modulate the endocannabinoid system in a more specific manner. In this research line we develop assays, mass spectrometry methods and activity-based probes to determine the activity of the endocannabinoid biosynthetic enzymes. We use different lead finding strategies, including high throughput screening, to identify and optimize molecules to control the activity of the enzymes in preclinical disease models. This project is funded in part by a grant from the Dutch Research Council Chemical Sciences (NWO-CW).

> Faculty of Science Profile Programme "Endocannabinoids"

Development of biomarkers for target engagement of GPCRs

Cannabinoid CB1 and CB2 receptors, which are activated by Δ9-tetrahydrocannabinol (THC), the main active ingredient in marijuana, belong to the class of G-protein-coupled receptors (GPCRs). These receptors are extensively studied for their therapeutic potential. We have recently reported the identification of a new class of highly potent and selective CB2 receptor modulators, which were active in in vivo models of neuropathic pain without inducing CB1-mediated psychotropic side effects. The aim of this research line is to develop biomarkers to study target engagement of the CB2 receptor in preclinical disease models. This project is performed in collaboration with Dr. L. Heitman and funded by a grant from the Dutch Research Council Chemical Sciences (NWO-CW).

Development of selective kinase inhibitors to treat leukaemia

In collaboration with the Netherlands Cancer Institute (NKI) we have identified kinase inhibitors that potentially can be used for the treatment of acute myeloid leukaemia. The goal of this project is to improve the compounds in a hit optimization program. This project is executed under the framework of the Cancer Drug Discovery Initiative, a public private partnership of Leiden University, Netherlands Cancer Institute and Pivot Park Screening Centre.

Generation of compound libraries for the European Lead Factory

The European Lead Factory is a large scale European Research Facility for the discovery of leads and chemical tools for the therapeutic validation of biological targets. Major pharmaceutical companies, small medium enterprises and academic partners collaborate in this public private partnership to enhance preclinical research for the discovery of new drug candidates. Part of this initiative is the generation of a Joint European Compound Collection that can be used for screening. We contribute to this collection by developing new compound libraries inspired by natural products that contain a high degree of chiral centers to access unexplored chemical space. The European Lead Factory is funded by the Innovative Medicines Initiative under grant agreement no 115489.

  1. Soethoudt, M., U. Grether, J. Fingerle, T.W. Grim, "Cannabinoid CB2 Receptor Ligand Profiling Reveals Biased Signaling and Off-target Activity", Nature Communications, 2016.
  2. Ogasawara, D., H. Deng, A. Viader, M.P. Baggelaar, A. Breman, H. den Dulk, A.M.C.H. van den Nieuwendijk, M. Soethoudt, et al., "Rapid and profound rewiring of brain lipid signaling networks by acute diacylglycerol lipase inhibition", Proceedings of the National Academy of Sciences, vol. 113, issue 1, pp. 26 - 33, 01/2016, 2015. DOI: 10.1073/pnas.1522364112
  3. Janssen, F.J., M.P. Baggelaar, J.J.A. Hummel, H.S. Overkleeft, B.F. Cravatt, D.L. Boger, M. van der Stelt, "Comprehensive Analysis of Structure–Activity Relationships of α-Ketoheterocycles as sn-1-Diacylglycerol Lipase α Inhibitors", Journal of Medicinal Chemistry, vol. 58, issue 24, pp. 9742 - 9753, 12/2015. DOI: 10.1021/acs.jmedchem.5b01627
  4. Baggelaar, M.P., P.J.P. Chameau, V. Kantae, J. Hummel, K.-L. Hsu, F. Janssen, T. van der Wel, M. Soethoudt, et al., "Highly Selective, Reversible Inhibitor Identified by Comparative Chemoproteomics Modulates Diacylglycerol Lipase Activity in Neurons", Journal of the American Chemical Society, vol. 137, issue 27, pp. 8851 - 8857, 07/2015. DOI: 10.1021/jacs.5b04883
  5. Baggelaar, M.P., F.J. Janssen, A.C.M. van Esbroeck, H. den Dulk, M. Allara, S. Hoogendoorn, R. McGuire, B.I. Florea, et al., "Development of an Activity-Based Probe and In Silico Design Reveal Highly Selective Inhibitors for Diacylglycerol Lipase-alpha in Brain", Angewandte Chemie-International Edition, vol. 52, no. 46, pp. 12081-12085, Nov 11, 2013. DOI: 10.1002/Anie.201306295

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