The expression of aquaporins (AQPs), a family of proteins that facilitate the transport of water, glycerol and hydrogen peroxide across the cell membrane, is known to potentiate cancer invasion and metastasis. Similarly, AQP expression levels have been shown to predict survival in patients, and play a role in tumour growth, angiogenesis and tumour cell migration. Therefore, AQPs are pivotal in cancer biology and are potential targets for drug development. Although pharmacological modulators of AQPs have been identified and tested for therapeutic potential, the drug discovery process has been severely hindered 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 made it possible to determine the high-resolution structures of previously intractable biological systems, as the requirement for sample quantity and homogeneity has been reduced. These developments therefore facilitate structural studies of integral membrane proteins, such as AQPs, in complex with putative drugs, which were previously very challenging. As AQP3-mediated H₂O₂ transport has been shown to be important for breast cancer cell migration, our aim is to synthesise novel inhibitors, investigate their potency in a breast cancer model, and determine their structure in complex with AQP3 using cryo-EM.

For further information about this HALRIC pilot project, please contact:

Karin Lindkvist
Lund University
Karin.Lindvist@med.lu.se