There are still many life-threatening diseases, such as Alzheimer’s disease, metabolic syndrome and cancer, for which there are no suitable therapies available. Mario van der Stelt aims to discover new molecules that can act as drug candidates for these type of diseases. He is also a member of the interdisciplinary research programme Society, Artificial Intelligence and Life Sciences (SAILS).

More information about Mario van der Stelt

Research summary

Van der Stelt, an expert in the field of medicinal chemistry, is a full professor and chair of Molecular Physiology at Leiden University. Besides this, he is a member of the interdisciplinary research programme Society, Artificial Intelligence and Life Sciences (SAILS). By developing and integrating innovative chemical biology tools and concepts in medicinal chemistry, he aims to innovate the drug discovery process with the ultimate goal to efficiently discover clinical candidates for cancer and brain disorders to improve human health. He draws from his experience as a project leader at Merck Research Laboratories (2004-2011), where he led drug discovery programs in various therapeutic areas, including cancer and neuroscience, for several target proteins, such as G Protein-coupled receptors (GPCRs) and kinases. 
                
Approximately only one out of ten clinical candidates currently reaches the market. Most compounds fail due to a lack of efficacy or unexpected off-target toxicity in clinical trials. Information on target engagement at a certain concentration will help to select the best molecule as a drug candidate and may guide the dose selection by providing information on full target engagement, while minimizing the risk for untoward off-target interactions by preventing overexposure.  This information is, however, often lacking for many drug discovery programs, due to a dearth of chemical tools and methods to establish target engagement in human cells. At Leiden University Van der Stelt develops chemical probes to be used in activity-based proteomic and chemical genetic strategies to determine on- and off-target profiles for compounds in biological systems.

• A first example of the integration of chemical biology concepts into drug discovery is his work on the fatty acid amide hydrolase (FAAH) inhibitor BIA 10-2474, an experimental drug developed by a Portuguese company, that caused the death of a volunteer in a phase 1 clinical trial in France in 2016. By using activity-based proteomics and targeted lipidomics in human cortical neurons and human brain tissue his lab discovered that BIA 10-2474 was a non-selective compound that interacted with several lipases and disrupted lipid homeostasis [Key output 1-2]. These findings were instrumental in the decision-making process to resume clinical trials with other safe FAAH inhibitors, which are currently being tested in major depressive disorder, social anxiety disorder and post-traumatic brain disorders. For this work, Van der Stelt received the prestigious Prix Galien Research Award for best preclinical drug discovery research in the Netherlands (2017). The impact of this technology is also witnessed by several collaborations he has established with small biotech start-up and large pharmaceutical companies to guide their drug optimization programs. This led to successful identification of a clinical candidate, which is currently tested in phase 1 clinical trials.
• A second example is the application of activity-based proteomics to guide the discovery of best-in-class ligands to investigate and validate the (patho)physiological function of proteins in brain lipid signaling [Key output 3]. He identified the first brain active inhibitors of proteins responsible for the biosynthesis of the endocannabinoids, thereby establishing the biological role of these lipid neurotransmitters in emotional behavior and neuroinflammation [Key output 4-6]. For this work, funded by a VICI-grant from the talent scheme of Dutch Research Council, he received the Young Investigator Award from the International Cannabinoid Research Society (2017) and the Utrecht University Award for Excellence in pharmaceutical research (2022).
• A third example is the discovery of the first-in-class bifunctional probes for the profiling of GPCRs, lipid signaling and aldehyde dehydrogenases (ALDHs) [Key output 7-9]. An important step that drives the drug discovery process is the determination of the cellular expression profile and engagement of the target protein in humans. This provides a challenge for the study of GPCRs and ALDHs, because they are usually expressed at very low levels in a dynamic manner in cells and tissues. Furthermore, GPCRs lack a catalytically nucleophilic amino acid that can be targeted by activity-based probes, thus rendering them inaccessible for activity-based protein profiling. Van der Stelt addressed this problem by designing and synthesizing a photoreactive probe equipped with a strategically positioned ligation tag for the introduction of reporter groups. In this manner he was the first to monitor the expression and engagement of the cannabinoid CB2 receptor, a promising GPCR to treat tissue injury and inflammatory diseases, upon photoactiviation in primary human immune cells using flow cytometry. The paper was highlighted by the editors and placed on the cover of JACS. Likewise, he developed a photoaffinity-based probe based on an oxidative metabolite of an omega-3 fatty acid and identified prostaglandin reductase-1 as a key metabolic hub in human macrophages [Key output 8]. ALDHs constitute a class of 19 enzymes responsible for detoxification of anti-cancer drugs and are upregulated as a resistance mechanism. No biochemical methods are available to detect specific aldehyde dehydrogenase activity in cells. Van der Stelt developed a first-in-class bifunctional, substrate-based probe that allowed to detect individual ALDH activities in breast cancer cells [Key output 9]. Together, these publications demonstrate the power of chemical probes to uncover new biology and serve as tools for target validation.        
• A fourth example is the development of a chemical genetics strategy to selectively study engagement of endogenously expressed kinases [Key output 10]. Kinases belong to a large druggable protein family for the treatment of cancer and autoimmune diseases, but the clinical development of kinase inhibitors is hampered by off-target effects and the difficulty establishing a causal relationship between on-target inhibition and phenotype. By substituting a serine residue into cysteine in the ATP-binding pocket, a kinase was sensitized towards covalent labeling by a complementary fluorescent chemical probe. The mutation was introduced in the genome of human cells by gene editing. Leveraging the temporal and acute control offered by the strategy, a key role for the kinase in neutrophil phagocytosis was uncovered. 

Finally, Van der Stelt is a member of the research management committee of Oncode Institute and architect of the small molecule workstream and the artificial intelligence platform. As coordinator of the small molecule workstream he assembled a public-private consortium that aims to generate clinical candidates for the treatment of cancer. Innovative concepts from the field of chemical biology will be integral part of the workstream to explore new chemical space for traditionally considered undruggable targets.

Key output

1. van Esbroeck A.C.M., Janssen A.P.A., Cognetta A.B., 3rd, Ogasawara D., Shpak G., van der Kroeg M., Kantae V., Baggelaar M.P., de Vrij F.M.S., Deng H., Allara M., Fezza F., Lin Z., van der Wel T., Soethoudt M., Mock E.D., den Dulk H., Baak I.L., Florea B.I., Hendriks G., De Petrocellis L., Overkleeft H.S., Hankemeier T., De Zeeuw C.I., Di Marzo V., Maccarrone M., Cravatt B.F., Kushner S.A., van der Stelt M., Activity-based protein profiling reveals off-target proteins of the FAAH inhibitor BIA 10-2474. Science 2017, 356 (6342), 1084-1087 doi: 10.1126/science.aaf7497
2. van Rooden E.J., Florea B.I., Deng H., Baggelaar M.P., van Esbroeck A.C.M., Zhou J., Overkleeft H.S., van der Stelt M. Mapping in vivo target interaction profiles of covalent inhibitors using chemical proteomics with label-free quantification. Nature Protoc. 2018, 13(4):752-767. doi: 10.1038/nprot.2017.159.
3. Punt J.M., van der Vliet D., van der Stelt M. Chemical Probes to Control and Visualize Lipid Metabolism in the Brain. Acc Chem Res. 2022 Nov 15;55(22):3205-3217. doi: 10.1021/acs.accounts.2c00521
4. Mock E.D., Mustafa M., Gunduz-Cinar O., Cinar R., Petrie G.N., Kantae V., Di X., Ogasawara D., Varga Z.V., Paloczi J., Miliano C., Donvito G., van Esbroeck A.C.M., van der Gracht A.M.F., Kotsogianni I., Park J.K., Martella A., van der Wel T., Soethoudt M., Jiang M., Wendel T.J., Janssen A.P.A., Bakker A.T., Donovan C.M., Castillo L.I., Florea B.I., Wat J., van den Hurk H., Wittwer M., Grether U., Holmes A., van Boeckel C.A.A., Hankemeier T., Cravatt B.F., Buczynski M.W., Hill M.N., Pacher P., Lichtman A.H., van der Stelt M. Discovery of a NAPE-PLD inhibitor that modulates emotional behavior in mice. Nature Chem Biol. 2020, 16(6):667-675 doi: 10.1038/s41589-020-0528-7
5. Ogasawara D., Deng H., Viader A., Baggelaar M.P., Breman A., den Dulk H., van den Nieuwendijk A.M., Soethoudt M., van der Wel T., Zhou J., Overkleeft H.S., Sanchez-Alavez M., Mori S., Nguyen W., Conti B., Liu X., Chen Y., Liu Q.S., Cravatt B.F., van der Stelt M. Rapid and profound rewiring of brain lipid signaling networks by acute diacylglycerol lipase inhibition. Proc Natl Acad Sci U S A. 2016, 113(1):26-33. doi: 10.1073/pnas.1522364112
6. Baggelaar M.P., Chameau P.J., Kantae V., Hummel J., Hsu K.L., Janssen F., van der Wel T., Soethoudt M., Deng H., den Dulk H., Allarà M., Florea B.I., Di Marzo V., Wadman W.J., Kruse C.G., Overkleeft H.S., Hankemeier T., Werkman T.R., Cravatt B.F., van der Stelt M. Highly Selective, Reversible Inhibitor Identified by Comparative Chemoproteomics Modulates Diacylglycerol Lipase Activity in Neurons. J Am Chem Soc. 2015, 137(27):8851-7. doi: 10.1021/jacs.5b04883
7. Soethoudt M., Stolze S.C., Westphal M.V., van Stralen L., Martella A., van Rooden E.J., Guba W., Varga Z.V., Deng H., van Kasteren S.I., Grether U., AP I.J., Pacher P., Carreira E.M., Overkleeft H.S., Ioan-Facsinay A., Heitman L.H., van der Stelt M. Selective Photoaffinity Probe That Enables Assessment of Cannabinoid CB2 Receptor Expression and Ligand Engagement in Human Cells. J Am Chem Soc 2018, 140 (19), 6067-6075. doi: 10.1021/jacs.7b11281
8. Gagestein B., von Hegedus J.H., Kwekkeboom J.C., Heijink M., Blomberg N., van der Wel T., Florea B.I., van den Elst H., Wals K., Overkleeft H.S., Giera M., Toes R.E.M., Ioan-Facsinay A., van der Stelt M. Comparative Photoaffinity Profiling of Omega-3 Signaling Lipid Probes Reveals Prostaglandin Reductase 1 as a Metabolic Hub in Human Macrophages. J Am Chem Soc. 2022, 144(41):18938-18947. doi: 10.1021/jacs.2c06827
9. Koenders S.T.A., Wijaya L.S., Erkelens M.N., Bakker A.T., van der Noord V.E., van Rooden E.J., Burggraaff L., Putter P.C., Botter E., Wals K., van den Elst H., den Dulk H., Florea B.I., van de Water B., van Westen G.J.P., Mebius R.E., Overkleeft H.S., Le Dévédec S.E., van der Stelt M. Development of a Retinal-Based Probe for the Profiling of Retinaldehyde Dehydrogenases in Cancer Cells. ACS Cent Sci. 2019, 5(12):1965-1974. doi: 10.1021/acscentsci.9b01022
10. van der Wel T., Hilhorst R., den Dulk H., van den Hooven T., Prins N.M., Wijnakker J.A.P.M., Florea B.I., Lenselink E.B., van Westen G.J.P., Ruijtenbeek R., Overkleeft H.S., Kaptein A., Barf T., van der Stelt M. Chemical genetics strategy to profile kinase target engagement reveals role of FES in neutrophil phagocytosis. Nat Commun. 2020 Jun 25;11(1):3216. doi: 10.1038/s41467-020-17027-5

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