A focus on P2X7 and P2X4 receptors The P2X7 receptor, an ion channel, has been well-explored in terms of ligand development, now researchers are seeking to explore its potential as a target for the treatment of different cancers and inflammatory diseases. We spoke to Dr Anna Junker about her work in contributing to the further improvement of diagnostics and therapies against breast cancer. important role in the development of some forms of cancer through stimulation of cell invasion and migration, and in inflammatory diseases through the release of interleukin 1ß (IL-1ß), a cytokine protein. As scientists have learned more about this specific receptor, part of the family of purinergic receptors, it has attracted increasing attention as a target for the treatment of these conditions. “We are always looking for new targets. P2X7R is quite wellexplored in terms of ligand development – more than 50 patents have been filed focusing on the development of P2X7R ligands for the treatment of inflammatory diseases,” outlines Dr Anna Junker, an Emmy-Noether research group leader at the University of Munster. This also represents a good starting point for developing PET tracers to assess the effectiveness of treatment, another important strand of Dr Junker’s research. “We develop tracers that can be used in in vivo settings for imaging,” she says. “When you have a mouse model of breast cancer and treat a mouse with an imaging agent targeting P2X7R, you can detect and monitor the progression or remission of the cancer.”
The students Clemens Dobelmann (Ph.D., right) and Maximilian Hagemann (MSc, left) analyzing the HPLC data.
Andreas Isaak (Ph.D.) performing synthesis.
P2X7 and P2X4 Receptors P2X7 and P2X4 Receptors in Cancer and Inflammation: Drug Development, Bioimaging, and Targeted Drug Delivery Funded through the Emmy Noether Programme of the Deutsche Forschungsgemeinschaft (DFG). Dr Anna Junker, European Institute for Molecular Imaging, Westfälische WilhelmsUniversität, Münster, Germany T: +49 251 8333363 E: anna.junker@uni-muenster.de W: https://www.uni-muenster. de/EIMI/de/research/junker-a. phps
Dr Anna Junker is an Emmy Noether Group Leader at the European Institute for Molecular Imaging in Munster. Alongside the P2X4 and P2X7 receptor ligands, her main research interests are the ligands for P1 and P2 receptors, stereoselective synthesis and the development and application of novel synthetic methods in medicinal chemistry.
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Photographs taken by Peter Dziemba.
The P2X7 receptor is known to play an
ligand if we want it to work as a fluorescent imaging agent than we do for PET imaging,” points out Dr Junker. “We also use some of the ligands that we develop in targeted drug delivery systems. So we essentially hook our ligand onto a drug delivery system, and try to achieve enrichment of the ligand in the area that the ligand should be delivered to.” A particular compound may be known to be potent, yet not function effectively because it is not delivered to the right part of the body, while an effective compound does not necessarily provide a good imaging agent, for example due to its rapid metabolism or excretion. In this type of situation, researchers may need to modify the compound in some way. “For example, we might need to increase the hydrophilicity or the lipophilicity of a compound or improve its metabolic stability. Usually, we modify various parameters that influence absorption, distribution, metabolism, and excretion (ADME) properties,” explains Dr Junker. The wider objective in this research is to develop more effective therapies against breast cancer and help minimize the sideeffects of treatment. It is known that P2X7R plays an important role in the development of triple-negative breast cancer. Dr Junker and her colleagues aim to contribute to improved
Andreas Isaak (Ph.D.) HPLC sample preparation.
We develop imaging tracers that can be used in in vivo settings to improve future diagnosis of breast cancer. Ligand design There are a number of different areas in Dr Junker’s research, with a lot of energy devoted to developing and improving ligands for both bioimaging and targeted drug delivery. A library of compounds has been generated and tested in vitro on cells, aiming to assess their effectiveness in inhibiting the P2X7 receptor. “Based on that we can analyse structure-activity relationships, and look to identify which modifications are better in terms of receptor inhibition,” outlines Dr Junker. This represents a step towards a more systematic approach, enabling scientists to precisely design ligands for specific purposes. “We have different requirements for the
treatment. “We want to help improve the diagnostics and potential therapies against breast cancer,” she says. A key step towards this is developing P2X7R-targeting tracers, which can then be evaluated in animal models. “We usually work with mice at our institute. We have a PET imaging system for mice constructed in the same way as the conventional system,” explains Dr Junker. “We usually use our compounds on mice, and when we find that the toxicological profile and the bio-distribution look satisfying, then we look at the disease model. If we find that the compounds perform well in the disease mouse model, then they can go forward for further investigations.”
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