2-Benzamido-N-(1H-benzo[d]imidazol-2-yl)thiazole-4-carboxamide derivatives as potent inhibitors of CK1d/e.

Amino acids

PubMedID: 22331384

Bischof J, Leban J, Zaja M, Grothey A, Radunsky B, Othersen O, Strobl S, Vitt D, Knippschild U. 2-Benzamido-N-(1H-benzo[d]imidazol-2-yl)thiazole-4-carboxamide derivatives as potent inhibitors of CK1d/e. Amino Acids. 2012;43(4):1577-91.
In this study we identified two heterocyclic compounds (5 and 6) as potent and specific inhibitors of CK1d (IC(50) = 0.040 and 0.042 µM, respectively). Whereas compound 5 exhibited fivefold higher affinity towards CK1d than to CK1e (IC(50) CK1e = 0.199 µM), compound 6 also inhibited CK1e (IC(50) = 0.0326 µM) in the same range as CK1d. Selected compound 5 was screened over 442 kinases identifying 5 as a highly potent and selective inhibitor of CK1d. X-ray analysis of 5 bound to CK1d 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 CK1d and e specific inhibitors with biological activity.