(Q)SAR studies to design new human choline kinase inhibitors as antiproliferative drugs

Most of the signal transduction pathways are mediated by protein kinases regulating every aspect of cell function. Mutations which deregulate their expression or their function or both result in cancers. Therefore, protein kinase inhibitors have become the ocus of development of new therapies for cancer. A comprehensive review of Choline kinase (ChoK) was published by us in 2003. Since then. molecular information of ChoK inhibitors has been accumulated. In this review, we intend to summarize the new lines of evidence that will include the design of the most active anti proliferative agents so far described against ChoK. Studies have been aimed at the establishment of structure-activity relationships and the structural parameters that define ChoK inhibitory and antiproliferative activities of a set of twenty-five acyclic biscationic pyridophane and forty acyclic biscationic quinolinephane compounds. The corresponding QSAR equation was obtained for the whole set of bisquinolinium compounds for the antiproliferative activity.. taking into consideration the electronic parameter sigma(R) of R-4, the molar refractivity (MR) of R-8. and the lipophilic parameters clog P and pi(linker). The most potent antiproliferative agent shows an IC50 = 0.45 mu M, predicted by the QSAR equation, whilst its experimental value is IC50 = 0.20 mu M. Finally, toxicity assays were performed for the most promising compounds because of their interesting antiproliferative activities [IC50 (HT-29) = 0.70, 0.80, 1.50 and 1.90 mu M] and low toxicity [LD50 = 16.7, 12.51 > 25 and > 20 mg/kg of mouse]. These biological activities justify further analysis for antitumoral assays under in vivo conditions.