title: A novel small molecule antagonist of choline kinase-α that simultaneously suppresses MAPK and PI3K/AKT signaling.
abstract: Choline kinase-α expression and activity are increased in multiple human neoplasms as a result of growth factor stimulation and activation of cancer-related signaling pathways. The product of choline kinase-α, phosphocholine, serves as an essential metabolic reservoir for the production of phosphatidylcholine, the major phospholipid constituent of membranes and substrate for the production of lipid second messengers. Using in silico screening for small molecules that may interact with the choline kinase-α substrate binding domain, we identified a novel competitive inhibitor, N-(3,5-dimethylphenyl)-2-[[5-(4-ethylphenyl)-1H-1,2,4-triazol-3-yl]sulfanyl] acetamide (termed CK37) that inhibited purified recombinant human choline kinase-α activity, reduced the steady-state concentration of phosphocholine in transformed cells, and selectively suppressed the growth of neoplastic cells relative to normal epithelial cells. Choline kinase-α activity is required for the downstream production of phosphatidic acid, a promoter of several Ras signaling pathways. CK37 suppressed mitogen-activated protein kinase and phosphatidylinositol 3-kinase/AKT signaling, disrupted actin cytoskeletal organization, and reduced plasma membrane ruffling. Finally, administration of CK37 significantly decreased tumor growth in a lung tumor xenograft mouse model, suppressed tumor phosphocholine, and diminished activating phosphorylations of extracellular signal-regulated kinase and AKT in vivo. Together, these results further validate choline kinase-α as a molecular target for the development of agents that interrupt Ras signaling pathways, and indicate that receptor-based computational screening should facilitate the identification of new classes of choline kinase-α inhibitors.
authors.affiliation: Department of Medicine, University of Louisville, Louisville, KY 40202, USA.
authors.forename: B F
authors.initials: BF
authors.lastname: Clem
authors.forename: A L
authors.initials: AL
authors.lastname: Clem
authors.forename: A
authors.initials: A
authors.lastname: Yalcin
authors.forename: U
authors.initials: U
authors.lastname: Goswami
authors.forename: S
authors.initials: S
authors.lastname: Arumugam
authors.forename: S
authors.initials: S
authors.lastname: Telang
authors.forename: J O
authors.initials: JO
authors.lastname: Trent
authors.forename: J
authors.initials: J
authors.lastname: Chesney
mesh_terms: D000081:Acetamides / Q000494:pharmacology*; D000199:Actins / Q000378:metabolism; D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002797:Choline Kinase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D019295:Computational Biology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006367:HeLa Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008958:Models, Molecular; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010767:Phosphorylcholine / Q000378:metabolism; D011487:Protein Conformation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000081:Acetamides; D000199:Actins; D004791:Enzyme Inhibitors; C561309:N-(3,5-dimethylphenyl)-2-((5-(4-ethylphenyl)-1H-1,2,4-triazol-3-yl)sulfanyl)acetamide; D014230:Triazoles; D010767:Phosphorylcholine; D019869:Phosphatidylinositol 3-Kinases; C517212:CHKA protein, human; D002797:Choline Kinase; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; D016283:Proto-Oncogene Proteins p21(ras)