title: Difluoro-dioxolo-benzoimidazol-benzamides as potent inhibitors of CK1δ and ε with nanomolar inhibitory activity on cancer cell proliferation.
abstract: Deregulation of CK1 (casein kinase 1) activity can be involved in the development of several pathological disorders and diseases such as cancer. Therefore, research interest in identifying potent CK1-specific inhibitors is still increasing. A previously published potent and selective benzimidazole-derived CK1δ/ε-specific inhibitor compound with significant effects on several tumor cell lines was further modified to difluoro-dioxolo-benzoimidazole derivatives displaying remarkable inhibitory effects and increased intracellular availability. In the present study, we identified two heterocyclic molecules as new CK1-specific inhibitor compounds with favorable physicochemical properties and notable selectivity in a kinome-wide screen. Being compared to other CK1 isoforms, these compounds exhibited advanced isoform selectivity toward CK1δ. Moreover, newly designed compounds showed increased growth inhibitory activity in a panel of different tumor cell lines as determined by analyses of cell viability and cell cycle distribution. In summary, presented lead optimization resulted in new highly selective CK1δ-specific small molecule inhibitors with increased biological activity.
authors.affiliation: Department of General and Visceral Surgery, Ulm University Hospital , Albert-Einstein-Allee 23, D-89081 Ulm, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Richter
authors.forename: Joachim
authors.initials: J
authors.lastname: Bischof
authors.forename: Mirko
authors.initials: M
authors.lastname: Zaja
authors.forename: Hella
authors.initials: H
authors.lastname: Kohlhof
authors.forename: Olaf
authors.initials: O
authors.lastname: Othersen
authors.forename: Daniel
authors.initials: D
authors.lastname: Vitt
authors.forename: Vanessa
authors.initials: V
authors.lastname: Alscher
authors.forename: Irmgard
authors.initials: I
authors.lastname: Pospiech
authors.forename: Balbina
authors.initials: B
authors.lastname: García-Reyes
authors.forename: Sebastian
authors.initials: S
authors.lastname: Berg
authors.forename: Johann
authors.initials: J
authors.lastname: Leban
authors.forename: Uwe
authors.initials: U
authors.lastname: Knippschild
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis* / Q000494:pharmacology; D048149:Casein Kinase 1 epsilon / Q000037:antagonists & inhibitors*; D048148:Casein Kinase Idelta / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D006801:Humans; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D048149:Casein Kinase 1 epsilon; D048148:Casein Kinase Idelta