Difluoro-dioxolo-benzoimidazol-benzamides as potent inhibitors of CK1δ and ε with nanomolar inhibitory activity on cancer cell proliferation.

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 specifc inhibitors is still increasing. A previously published potent and selective benzimidazole-derived CK1 delta/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 CK-specific inhibitor compunds with favorable physicochemical properties and notable selectivity in a kinom-wide screen Being compared to other CK1 isoforms these compounds exhibited advanced isoform selectivity toward CK1 delta 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 elective CK1 delta-specific small molecule inhibitors with increased biological activity.