Breast cancer is one of the leading causes of mortality in the female population. Despite improvement in procedures and treatment, drastic increases in survival rates are still lacking. The overall aim of this project is to use structure- based drug design to improve the inhibitors targeting specific aquaporins (AQPs), a family of proteins that facilitate the transport of water/glycerol and hydrogen peroxide across the cell membrane.
Cancer invasion and metastasis are known to be potentiated by the expression of AQPs and likewise, the expression levels of AQPs have been shown to be prognostic for survival in patients and have a role in tumor growth, angiogenesis, and tumor cell migration. Thus, AQPs are key players in cancer biology and potential targets for drug development. Pharmacological modulators of AQPs have been identified and tested for therapeutic potential, however, the drug discovery process has been severely hampered by the lack of three-dimensional structures of AQPs in complex with inhibitors.
The so called ‘resolution revolution’ in single particle cryo-electron microscopy (cryo-EM) has opened the door for determination of high-resolution structures of previously intractable biological systems based on the reduced requirement for both quantity and homogeneity of samples. Thus, these developments facilitate the possibility to execute structural studies of integral membrane proteins, like AQPs, in complex with putative drugs that was previously very challenging. As AQP3-mediated H2O2 transport has been shown to be important for breast cancer cell migration, the research team aims to investigate the potency of AQP3 inhibitors in a breast cancer model and determine the structure of these inhibitors in complex with AQP3 applying cryo-EM.
The pilot project has a unique cross-border composition to enable the possibility to use cryo-EM to execute structural analysis of aquaporin inhibitors and validate those in breast cancer models. The research team is composed of experts in the structural biology of aquaporins on the Swedish side at Lund University and of experts in cryo-EM analysis as well as in breast cancer and in vitro models of breast cancer at Aarhus University on the Danish side. Furthermore, the industry partner Apoglyx AB develops aquaporin blockers to be used as therapeutics and the company will bring a focus on translating academic results concerning AQP inhibitors into therapies for human conditions with high unmet medical needs.
For further information about this HALRIC pilot project, please contact:
Karin Lindkvist
Lund University
Karin.Lindvist@med.lu.se
Raminta Venskutonyte
Lund University
Raminta.Venskutonyte@med.lu.se