For a rapidly dividing cell it is necessary to be able to synthesize phospholipids at a high rate to satisfy the needs for cell membrane formation. One of the most abundant phospholipids in the eukaryotic cell membrane is phosphatidyl choline (PC). The first step in the biosynthesis of PC is the phosphorylation of choline by the choline kinase class of enzymes. A number of evidence pinpoints the role of choline kinase activity in cellular transformation (Gallego-Ortega et al., 2011). In several cancer forms the ChoKa gene is up-regulated to support the need for PC synthesis. Indeed, radiolabelled choline have also been used for PET imaging of tumors, primarily in the brain and the prostate, confirming that this metabolite is selectively taken up and retained in the tumor cells (Glunde & Bhujwalla, 2011).
Choline kinase:
We are running a fragment-based drug discovery program to target Choline kinase α. A fragment screen has been performed and several chemical series with different mode-of-action have been identified. Crystal structure determination and thermodynamic profiling of fragment hits and hit analogues have been performed. We have established a biochemical assay and are currently running a structure-based fragment expansion program.
References
- Gallego-Ortega, D., del Pulgar, T.G., Valdés-Mora, F., Cebrián, A., Lacal, J.C. (2011) Adv Enzyme Regul. 51:183-94.
- Glunde, K., Bhujwalla, Z.M. (2011) Semin Oncol. 38:26-41.
