Abnormal lipid metabolism is a common feature of cancers. In the clinic, elevated phosphocholine, an essential membrane lipid precursor, is revealed as a phenotype associated with malignant lipid metabolism. Overexpression of choline kinase alpha isoform (CHKA), is recognised as a predominant factor responsible for the phenotype, and, therefore, CHKA has become a novel therapeutic target for cancer. In the previous work by Trousil et al., a potent CHKA inhibitor ICL-CCIC-0019 was reported, which displayed high cellular activity but undesirable pharmacological properties to be ameliorated. In this thesis, CK146, an active analogous scaffold of ICL-CCIC-0019, bearing a reactive piperazine handle, is presented. This novel scaffold opens the further possibilities for structural elaboration of the classic pharmacophore by innovatively exploiting two advanced drug development strategies. In the first strategy, selective CHKA inhibition was attempted to be achieved by prodrug CK145, via the incorporation of an ε-(Ac)Lys motif into CK146. In the second strategy, a peptide ligand targeting prostate-specific membrane antigen (PSMA) receptor was embodied in CK146 to afford CK147, aimed to realise the targeted delivery to the malignant cells with high expression of PSMA receptors on cell surface.

As expected, the precursor scaffold CK146 displayed high CHKA activity in kinase screening (CHKA activity as part of a 15 human lipid kinase screen: CK146: 69%, ICL-CCIC-0019: 53%) and good antiproliferative activity against four selected cancer cell lines (overall GI50 against HCT-116, A549, HepG2 and Caco-2: CK146: 2.5 ± 0.3 μM, ICL-CCIC-0019: 0.5 ± 0.02 μM). Proposed prodrug CHKA inhibitor (CK145) and PSMA-targeted CHKA inhibitor (CK147) were successfully synthesised. The pharmacological activity and pharmacokinetic profiles of the obtained compounds were evaluated in vitro. Although attempts to improve the pharmacological profiles of ICL-CCIC-0019 were not effective by these two modification strategies, important and informative structure-activity relationships were concluded and have been reported.