Universiteit Leiden

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Reedijk Symposium 2019: Chemical probes in drug discovery

Friday 25 October 2019
Gorlaeus Building
Einsteinweg 55
2333 CC Leiden


The success of new drugs depends on our ability to understand their molecular and cellular mechanism of action. Modulation of cannabinoid CB1 and CB2 receptors activity by endogenous lipid messengers, termed endocannabinoids, is associated with therapeutic benefits in humans. Poor understanding of the physiological role of endocannabinoids and lack of detailed selectivity profiling of experimental drugs, however, led to the market withdrawal of Acomplia®, a CB1 receptor antagonist, and the death of one volunteer in a phase 1 clinical trial exposed to the FAAH inhibitor BIA 10-2474. To assess the therapeutic potential of the endocannabinoid system and its drugs, we have developed and characterized b-lactone-based activity-based probes and a photoaffinity probe that targets brain lipases and the cannabinoid CB2 receptor, respectively. In a competitive activity-based proteomics format these tailor-made probes were employed to discover the first brain active inhibitors of endocannabinoid biosynthesis (1-3), reported the off-target landscape of BIA 10-2474 (4) and to profile CB2 receptor expression and its ligands in human cells (5-6). Here, I will present our recent results on the discovery of the first in vivo active inhibitors of the enzyme NAPE-PLD, an important player in endocannabinoid biosynthesis.


  1. Baggelaar et al. J. Am. Chem. Soc, 2015, 137, 8851
  2. Ogasawara et al., Proc. Natl. Acad. Sci., 2016, 113, 26
  3. Van Rooden en al., Nature Prot. 2018, 13, 752
  4. Van Esbroeck et al., Science, 2017, 356, 1084
  5. Soethoudt et al., J. Am. Chem. Soc, 2018, 140,14192
  6. Soethoudt et al. Nature Comm., 2017, Jan 3, 13958
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