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-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.