title: Discovery of a new binding site on human choline kinase α1: design, synthesis, crystallographic studies, and biological evaluation of asymmetrical bispyridinium derivatives.
abstract: Human choline kinase α (CKα) is a validated drug target for the treatment of cancer. In recent years, a large number of CK inhibitors have been synthesized, and one of them is currently being evaluated in Phase I clinical trials as a treatment for solid tumors. Here we have evaluated a new series of asymmetrical biscationic CK inhibitors by means of enzymatic, crystallographic, and antitumor studies. We demonstrate that one of these structures adopts a completely new binding mode not observed before inducing the aperture of an adjacent binding site. This compound shows antiproliferative and apoptotic effects on cancer cells through activation of caspase-3. Therefore, this study not only provides fruitful insights into the design of more efficient compounds that may target different regions in CKα1 but also explains how these compounds induce apoptosis in cancer cells.
authors.affiliation: Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, Universidad de Granada , Campus de Cartuja s/n, 18071 Granada, Spain.
authors.forename: Belén
authors.initials: B
authors.lastname: Rubio-Ruiz
authors.forename: Ainoa
authors.initials: A
authors.lastname: Figuerola-Conchas
authors.forename: Javier
authors.initials: J
authors.lastname: Ramos-Torrecillas
authors.forename: Fermín
authors.initials: F
authors.lastname: Capitán-Cañadas
authors.forename: Pablo
authors.initials: P
authors.lastname: Ríos-Marco
authors.forename: Ma Paz
authors.initials: MP
authors.lastname: Carrasco
authors.forename: Miguel Ángel
authors.initials: MÁ
authors.lastname: Gallo
authors.forename: Antonio
authors.initials: A
authors.lastname: Espinosa
authors.forename: Carmen
authors.initials: C
authors.lastname: Marco
authors.forename: Concepción
authors.initials: C
authors.lastname: Ruiz
authors.forename: Antonio
authors.initials: A
authors.lastname: Entrena
authors.forename: Ramon
authors.initials: R
authors.lastname: Hurtado-Guerrero
authors.forename: Ana
authors.initials: A
authors.lastname: Conejo-García
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis; D001665:Binding Sites; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002797:Choline Kinase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D018360:Crystallography, X-Ray; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation; D006367:HeLa Cells; D006801:Humans; D062105:Molecular Docking Simulation; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D011725:Pyridines; C517212:CHKA protein, human; D002797:Choline Kinase; D053148:Caspase 3