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Mario van der Stelt and Laura Heitman have been awarded an NWO ECHO-STIP grant

On Friday May 3rd 2013 NWO has announced that Dr. Mario van der Stelt, Division of Bio-Organic Synthesis (LIC) and Dr. Laura Heitman, Division of Medicinal Chemistry (LACDR), have been awarded with an ECHO-STIP grant for their project, entitled: “Novel target engagement biomarkers for better drug candidates”.

Novel target engagement biomarkers for better drug candidates

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. Dr. Van der Stelt has recently discovered 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 proposal is to leverage these findings and use the novel CB2-receptor selective scaffold to design, synthesize and characterize new photoaffinity-based chemical probes for the CB2 receptor. These probes can be used to study target engagement of the CB2 receptor in preclinical disease models to increase confidence in the CB2-receptor as a valid therapeutic target.

Traditionally, the development of highly potent photo-affinity-based probes of GPCRs has been hampered by a lack of structural information of the GPCR to appropriately position the photoreactive group in the ligand to ensure an optimal interaction and efficient labeling of the protein. We will exploit our knowledge of the structure activity relationships of our ligands and recent breakthroughs in 3D structure information of GPCRs, to guide the design and chemical synthesis of new photoaffinity-based imaging probes for the CB2 receptor. In addition, another innovative aspect of the project is the planned residence time studies with these CB2 receptor ligands, which have been developed by Dr. Heitman. This will improve their on-target photo-cross linking and by incorporating structure-kinetic-relationships, we will select the best compound based on its receptor residence time. A bio-orthogonal two-step labeling approach will be used to maintain specificity and bioavailability of the probes, thereby making them suitable for in vivo studies. It is envisaged that the probes may help to bring forward new CB2-receptor-based therapeutics. Once successful, this approach can also be extended to other therapeutically relevant GPCRs.

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