Recent advances in the design of choline kinase α inhibitors and the molecular basis of their inhibition

Abstract

Up-regulated choline metabolism, characterized by an increase in phosphocholine (PCho), is a hallmark of oncogenesis and tumor progression. Choline kinase (ChoK), the enzyme responsible for PCho synthesis, has consequently become of a promising drug target for cancer therapy and as such a significant number of ChoK inhibitors have been developed over the last few decades. More recently, due to the role of this enzyme in other pathologies, ChoK inhibitors have also been used in new therapeutic approaches against malaria and rheumatoid arthritis. Here, we review research results in the field of ChoKα inhibitors from their synthesis to the molecular basis of their binding mode. Strategies for the development of inhibitors and their selectivity on ChoKα over ChoKβ, the plasticity of the choline-binding site, the discovery of new exploitable binding sites, and the allosteric properties of this enzyme are highlighted. The outcomes summarized in this review will be a useful guide to develop new multi-functional potent drugs for the treatment of various human diseases.

ChoK-Full of Potential: Choline Kinase in B Cell and T Cell Malignancies

“…Chka −/− mice die early in embryogenesis, while Chkb −/− mice survive to adulthood but develop hindlimb muscular dystrophy and forelimb bone deformity, suggesting a broader function for Chkα than Chkβ [ 9 , 12 , 13 ]. In line with this, CHKα overexpression has been detected in a wide variety of human cancers, including breast, prostate, lung, colon, liver, head and neck, esophageal, stomach, bladder, ovary, skin and brain cancers, with an incidence of 40–60% in all tumors investigated [ 3 , 6 , 9 ]. Major mechanisms leading to CHKα overexpression include amplification of the CHKA gene, activation of oncogenic signaling pathways and epigenetic alterations (such as HDACs) [ 1 , 9 , 11 , 14 , 15 , 16 , 17 ].…”

“…Aberrant choline metabolism, characterized by an increase in total choline-containing compounds (tCho), phosphocholine (P-Cho) and phosphatidylcholine (PC), is a metabolic hallmark of carcinogenesis and tumor progression [ 1 , 2 , 3 , 4 , 5 , 6 ]. Phosphatidylcholine is the most abundant phospholipid of all mammalian cell types and subcellular organelles, comprising ~50% of total cellular phospholipids [ 7 , 8 ].…”

“…Therefore, MRS-based measurement of choline metabolism has been useful in clinical diagnosis and treatment monitoring of cancer patients [ 1 , 2 , 3 , 4 ]. Mechanistic investigation has elucidated that the molecular causes of aberrant choline metabolism in cancers arise from alterations in enzymes that control the anabolic and catabolic pathways of PC, including choline kinase α (CHKα), PC-specific phospholipase C (PC-PLC), PC-PLD1 and glycerophosphocholine phosphodiesterases (GPCPDs), which are often associated with up-regulated expression and activity of several choline transporters [ 1 , 2 , 4 , 6 ]. Thus, these metabolic enzymes and choline transporters have been identified as important therapeutic targets for anti-cancer therapy, either alone or in combination with other cancer therapies [ 1 , 2 , 4 , 6 ].…”

“…Among all the enzymes that control choline metabolism, CHKα exhibits the most frequent alterations in human cancers [ 1 , 3 , 6 , 9 ]. Choline kinase is a cytosolic enzyme that catalyzes the phosphorylation of choline to generate P-Cho in the presence of ATP and magnesium, the first step in de novo PC biosynthesis termed the Kennedy pathway [ 9 , 10 , 11 ].…”

“…Examples of oncogenic pathways that induce the up-regulation of CHKα are Ras-Raf-MAPK-AP1, PI3K-mTOR-Akt, EGFR-PI3K-Akt, Bcr-Abl-MEK-ERK/PI3K-Akt, and c-Kit-Ras-Raf-MAPK/PI3K-Akt [ 1 , 9 , 11 , 16 ]. CHKα overexpression is associated with the malignant phenotype, metastatic capability and drug resistance in human cancers, and thus has been recognized as a robust biomarker in cancer [ 3 , 6 , 11 , 18 ]. Interestingly, therapeutic targeting of CHKα in cancer models has revealed a complex reciprocal interaction between oncogenic signaling pathways and choline metabolism [ 1 , 3 , 15 ].…”