National Center for
4TW9: Difluoro-dioxolo-benzoimidazol-benzamides As Potent Inhibitors Of Ck1delta And Epsilon With Nanomolar Inhibitory Activity On Cancer Cell Proliferation
Difluoro-dioxolo-benzoimidazol-benzamides As Potent Inhibitors of CK1delta and epsilon with Nanomolar Inhibitory Activity on Cancer Cell Proliferation
J. Med. Chem. (2014) 57 p.7933-7946
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 CK1delta/epsilon-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 CK1delta. 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 CK1delta-specific small molecule inhibitors with increased biological activity.