Leiden University

Mario van der Stelt (1975) is professor and chair of the department of Molecular Physiology of the Leiden University (the Netherlands). He is a medicinal chemist and worked as a project leader for almost 8 years in the pharmaceutical industry (Merck Research Laboratories). He and his group discovered highly selective and peripherally restricted cannabinoid CB2 receptor agonists and the first brain active inhibitors for the biosynthesis of endocannabinoids. His group reported the off-target profile of the FAAH inhibitor BIA 10-2474 that killed a healthy volunteer in a phase 1 clinical trial in France in 2016. Dr. Van der Stelt received for his research the Prix Galien Research for best preclinical drug discovery research in the Netherlands (2017), the Young Investigator Award of the International Cannabinoid Research Society (2017) and a VICI-award from the Netherlands Organisation for Scientific Research (2018). He is elected as a senior investigator of Oncode Institute (2019) and (vice)-chair of the Gordon Research Conference on Cannabinoid Function in the CNS (2021-2023). Multidisciplinary collaboration is key in his research to connect chemistry and biology to discover drug candidates modulating the endocannabinoid system.

• 2000 Coy W. Waller Award, ICRS meeting, Baltimore, USA

• 2001 Coy W. Waller Award, ICRS meeting Madrid, Spain

• 2001 Bijvoet PhD-competition Award, Utrecht, the Netherlands

• 2003 Young Investigator Award from the European Society for Neuroscience, Krakow, Poland

• 2005 Young Investigator Award from International Cannabis Association as Medicine, Leiden, NL

• 2017 Prix Galien Research for best preclinical drug discovery research in the Netherlands

• 2018 Young Investigator Award from the ICRS for major contributions to cannabinoid research

• 2018 VICI-award (1.5 M Euro) from the Netherlands Research Council

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 EJ, Florea BI, Deng H, Baggelaar MP, van Esbroeck ACM, Zhou J, Overkleeft HS, 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 JM, 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 ED, Mustafa M, Gunduz-Cinar O, Cinar R, Petrie GN, Kantae V, Di X, Ogasawara D, Varga ZV, Paloczi J, Miliano C, Donvito G, van Esbroeck ACM, van der Gracht AMF, Kotsogianni I, Park JK, Martella A, van der Wel T, Soethoudt M, Jiang M, Wendel TJ, Janssen APA, Bakker AT, Donovan CM, Castillo LI, Florea BI, Wat J, van den Hurk H, Wittwer M, Grether U, Holmes A, van Boeckel CAA, Hankemeier T, Cravatt BF, Buczynski MW, Hill MN, Pacher P, Lichtman AH, 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 MP, Breman A, den Dulk H, van den Nieuwendijk AM, Soethoudt M, van der Wel T, Zhou J, Overkleeft HS, Sanchez-Alavez M, Mori S, Nguyen W, Conti B, Liu X, Chen Y, Liu QS, Cravatt BF, 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 MP, Chameau PJ, Kantae V, Hummel J, Hsu KL, Janssen F, van der Wel T, Soethoudt M, Deng H, den Dulk H, Allarà M, Florea BI, Di Marzo V, Wadman WJ, Kruse CG, Overkleeft HS, Hankemeier T, Werkman TR, Cravatt BF, 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 JH, Kwekkeboom JC, Heijink M, Blomberg N, van der Wel T, Florea BI, van den Elst H, Wals K, Overkleeft HS, Giera M, Toes REM, 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 STA, Wijaya LS, Erkelens MN, Bakker AT, van der Noord VE, van Rooden EJ, Burggraaff L, Putter PC, Botter E, Wals K, van den Elst H, den Dulk H, Florea BI, van de Water B, van Westen GJP, Mebius RE, Overkleeft HS, Le Dévédec SE, 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 NM, Wijnakker JAPM, Florea BI, Lenselink EB, van Westen GJP, Ruijtenbeek R, Overkleeft HS, 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.

Sebastian Pomplun studied Chemistry and Pharmaceutical Technologies at the University Sapienza, in Rome. In his doctoral studies in organic and medicinal chemistry at the Max-Planck-Institute of Psychiatry in Munich (supervised by Prof. Felix Hausch) he developed asymmetric synthesis strategies for caged bicylic inhibitors of the psychiatric risk factor protein FKBP51. The resulting PhD thesis was awarded with Summa cum Laude in 2015. Sebastian then joined the Chemistry R&D department of Roche Diagnostics GmbH in Penzberg, Germany, as a postdoctoral research scientist. He developed novel bioconjugation reagents, cleavable linkers for peptides and functional building blocks for nanopore sequencing strategies. In 2019 Sebastian received a postdoctoral fellowship from the German Research Foundation (DFG) and joined the Pentelute Lab at the Massachusetts Institute of Technology in Cambridge, USA. At MIT he worked on rational and combinatorial strategies for the discovery of biohybrid molecules targeting disease related nucleic acids. In September 2021 Sebastian started as a tenure track assistant professor at the Leiden Academic Centre for Drug Research (LACDR) at Leiden University. His research is funded by LACDR, an ERC Starting Grant, NWO open competition funding and by the Oncode Accelerator program. Since 2024 Sebastian is a junior investigator in the Oncode Institute. https://pomplunlab.com/ 

• ERC-StG-2021 SynTra

1. Sebastian Pomplun, Muhammad Jbara, Carly Schissel, Ann Boija, Susanne Wilson Hawken, Isaac Klein, and Bradley L. Pentelute; Parallel automated flow synthesis of covalent protein complexes that inhibit MYC-driven transcription; ACS Central Science, 2021, 7, 8, 1408–1418 (OPEN ACCESS) https://doi.org/10.1021/acscentsci.1c00663

2. Sebastian Pomplun, Zachary P. Gates, Genwei Zhang, Anthony J. Quartararo, and Bradley L. Pentelute; Discovery of nucleic acid binding molecules from combinatorial biohybrid nucleobase peptide libraries; JACS, 2020, 2020, 142, 46, 19642–19651, (highlighted as front cover), https://doi.org/10.1021/jacs.0c08964

3. Sebastian Pomplun, Muhammad Jbara, Anthony J. Quartararo, Genwei Zhang,Joseph Brown, Yen-Chun Lee, Xiyun Ye, Stephanie Hanna and Bradley L. Pentelute; De Novo Discovery of High Affinity Peptide Binders for the SARS-CoV-2 Spike Protein; ACS Central Science, 2021, 7, 1, 156–163; (OPEN ACCESS) https://doi.org/10.1021/acscentsci.0c01309

4. Sebastian Pomplun*, Mohamed YH Mohamed, Tobias Oelschlaegel, Christian Wellner, Frank Bergmann; Efficient Pictet Spengler Bioconjugation with N-Substituted Pyrrolyl Alanine Derivatives; Angew. Chem. Int. Ed., 2019, 58 (11), 3542; (*corresponding author); https://doi.org/10.1002/anie.201814200

5. J. Miguel Mata,⁺  Edith van der Nol,⁺ and  Sebastian J. Pomplun*; Advances in Ultrahigh Throughput Hit Discovery with Tandem Mass Spectrometry Encoded Libraries; JACS, 2023, (OPEN ACCESS) https://doi.org/10.1021/jacs.3c04899; (⁺ = equal contribution)

I focus on the theme “Novel receptor concepts to target membrane proteins” that has the potential for a large societal impact. I have selected membrane-bound proteins, such as G protein-coupled receptors (GPCRs), as many drugs act via these. I have been able to develop an array of novel in vitro equilibrium and kinetic binding assays, as well as (label-free) functional assays to investigate my research theme, with the ultimate aim to make medicines work better.

Within the field of GPCRs I am both nationally and internationally recognized as a leader, as shown by several top publications in this field (see ‘selected publications’ below). From the start of my career, i.e. as a PhD student, and by obtaining several competitive research grants (e.g. NWO-VENI, NWO-VIDI, IMI-K4DD), I have been able to independently build my own research line along two novel receptor concepts in particular, i.e. ‘Allosteric modulation of GPCRs’ and ‘Drug-target binding kinetics’. Together, these two concepts culminated in a 2016 Nature paper where we were able to identify a novel intracellular binding site for small molecule antagonists at the chemokine receptor CCR2. Interestingly, a consequence of both concepts is so-called insurmountable antagonism, i.e. antagonists that cannot be disrupted/counteracted by high local concentrations of the endogenous receptor agonist that is often causal to.

To this end, we combine and integrate different expertise and research domains relevant for modern future molecular pharmacology, such as receptor pharmacology, molecular and cellular biology, organic chemistry and computational chemistry. Here the implementation of future key technologies and methodologies is crucial, such as high throughput kinetic binding and signaling assays, both at cell membranes and on living cells. My team collaborates with crystallographers, cell biologists and in vivo pharmacologists, both from academia and pharmaceutical industry. Of note, medicinal chemistry research in academia typically has few, if any, links with the clinic, but the concepts that I work on have a large translational potential. Hence, I keep a keen eye on collaborating with research hospitals and pharmaceutical companies to go from an idea to proof-of-concept and continue to make my research translational in nature, next to being fundamental.

• 2018: Oncode Junior Investigator (600 k€)

• 2018: Prix Galien Research award 2018 (runner-up)

• 2018: NWO-VIDI “Rethinking drug discovery – target binding kinetics as an essential paradigm” (800 k€)

• 2018: Prize for a Young Medicinal Chemist in Academia by European Federation of Medicinal Chemistry (runner-up)

• 2017: MedChemComm Emerging Investigator 2017 award by Royal Society of Chemistry

• 2015: RPF “Establishment of structure-kinetics relationships to elucidate the mode of action of CB2 ligands” (233 k€)

• 2013: IWT-O&O “Kinetic profiling as a novel concept for GPCR drug action” (294 k€)

• 2012: Best lecturer at Leiden University by the Leiden Student Council (runner-up)

• 2011: IMI "Kinetics for Drug Discovery" (1 M€)

• 2010: NWO-VENI “Why do drugs fail in man? Drug-target residence time as a novel parameter in drug design and discovery” (250 k€)

• 2009: “Discoverer of the Year 2009”-award from the Faculty of Science of Leiden University

1. Zheng Y, Qin L, Zacarías NV, de Vries H, Han GW, Gustavsson M, Dabros M, Zhao C, Cherney RJ, Carter P, Stamos D, Abagyan R, Cherezov V, Stevens RC, IJzerman AP, Heitman LH^#, Tebben A, Kufareva I^#, Handel TM^#. Structure of CC chemokine receptor 2 with orthosteric and allosteric antagonists. Nature. 2016, 540, 458 (^#shared senior author)

2. Liu W, Chun E, Thompson AA, Chubukov P, Xu F, Katritch V, Han GW, Roth CB, Heitman LH, IJzerman AP, Cherezov V, Stevens RC. Structural basis for allosteric regulation of GPCRs by sodium ions. Science. 2012, 337, 232-236

3. Soethoudt M*, Grether U*, Fingerle J*, Grim TW, Fezza F, de Petrocellis L, Ullmer C, Rothenhausler B, Perret C, van Gils N, Finlay D, MacDonald C, Chicca A, Gens MD, Stuart J, de Vries H, Mastrangelo N, Xia L, Alachouzos G, Baggelaar M, Martella A, Mock ED, Deng H, Heitman LH^#, Connor M^#, di Marzo V^#, Gertsch J^#, Lichtman AH^#, Maccarrone M^#, Pacher P^#, Glass M^#, van der Stelt M^#. Cannabinoid CB2 Receptor Ligand Profiling Reveals Biased Signaling and Off-target Activity: Implications for Drug Discovery. Nat Commun. 2017, 8, 13958 (^#shared senior author)

4. Bot I*, Ortiz Zacarías NV*, de Witte WE, de Vries H, van Santbrink PJ, van der Velden D, Kröner MJ, van der Berg DJ, Stamos D, de Lange EC, Kuiper J, IJzerman AP, Heitman LH. A novel CCR2 antagonist inhibits atherogenesis in apoE deficient mice by achieving high receptor occupancy. Sci. Rep. 2017, 7, 52

5. Vlachodimou A, IJzerman AP, Heitman LH.Label-free detection of transporter activity via GPCR signalling in living cells: A case for SLC29A1, the equilibrative nucleoside transporter 1. Sci Rep. 2019, 9, 13802