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2-Benzamido-N-(1H-benzo[d]imidazol-2-yl)thiazole-4-carboxamide derivatives as potent inhibitors of CK1?/?.

ABSTRACT: In this study we identified two heterocyclic compounds (5 and 6) as potent and specific inhibitors of CK1? (IC(50) = 0.040 and 0.042 ?M, respectively). Whereas compound 5 exhibited fivefold higher affinity towards CK1? than to CK1? (IC(50) CK1? = 0.199 ?M), compound 6 also inhibited CK1? (IC(50) = 0.0326 ?M) in the same range as CK1?. Selected compound 5 was screened over 442 kinases identifying 5 as a highly potent and selective inhibitor of CK1?. X-ray analysis of 5 bound to CK1? 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? and ? specific inhibitors with biological activity.

SUBMITTER: Bischof J

PROVIDER: S-EPMC3448056 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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

Bischof Joachim J Leban Johann J Zaja Mirko M Grothey Arnhild A Radunsky Barbara B Othersen Olaf O Strobl Stefan S Vitt Daniel D Knippschild Uwe U

Amino acids 20120214 4

In this study we identified two heterocyclic compounds (5 and 6) as potent and specific inhibitors of CK1δ (IC(50) = 0.040 and 0.042 μM, respectively). Whereas compound 5 exhibited fivefold higher affinity towards CK1δ than to CK1ε (IC(50) CK1ε = 0.199 μM), compound 6 also inhibited CK1ε (IC(50) = 0.0326 μM) in the same range as CK1δ. Selected compound 5 was screened over 442 kinases identifying 5 as a highly potent and selective inhibitor of CK1δ. X-ray analysis of 5 bound to CK1δ demonstrated ...[more]

PMID: 22331384

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