2-Benzamido-N-(1H-benzo[d]imidazol-2-yl)thiazole-4-carboxamide derivatives as potent inhibitors of CK1δ/ε

In this study we identified two heterocyclic compounds (5 and 6) as potent and specific inhibitors of CK1 delta (IC50 = 0.040 and 0.042 mu M, respectively). Whereas compound 5 exhibited fivefold higher affinity towards CK1 delta than to CK1 epsilon (IC50 CK1 epsilon = 0.199 mu M), compound 6 also inhibited CK1 epsilon (IC50 = 0.0326 mu M) in the same range as CK1 delta. Selected compound 5 was screened over 442 kinases identifying 5 as a highly potent and selective inhibitor of CK1 delta. X-ray analysis of 5 bound to CK1 delta demonstrated its binding mode. In addition, characterization of 5 and 6 in a cell biological approach revealed the ability of both compounds to inhibit proliferation of tumor cell lines in a dose and cell line specific manner. In summary, our optimizations lead to the development of new highly selective CK1 delta and epsilon specific inhibitors with biological activity.