title: 2-Benzamido-N-(1H-benzo[d]imidazol-2-yl)thiazole-4-carboxamide derivatives as potent inhibitors of CK1δ/ε.
abstract: 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 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 CK1δ and ε specific inhibitors with biological activity.
authors.affiliation: Department of General, Visceral and Transplantation Surgery, Surgery Centre, University of Ulm, Steinhövel Str. 9, 89075, Ulm, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Bischof
authors.forename: Johann
authors.initials: J
authors.lastname: Leban
authors.forename: Mirko
authors.initials: M
authors.lastname: Zaja
authors.forename: Arnhild
authors.initials: A
authors.lastname: Grothey
authors.forename: Barbara
authors.initials: B
authors.lastname: Radunsky
authors.forename: Olaf
authors.initials: O
authors.lastname: Othersen
authors.forename: Stefan
authors.initials: S
authors.lastname: Strobl
authors.forename: Daniel
authors.initials: D
authors.lastname: Vitt
authors.forename: Uwe
authors.initials: U
authors.lastname: Knippschild
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D048149:Casein Kinase 1 epsilon / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D048148:Casein Kinase Idelta / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D051379:Mice; D008958:Models, Molecular; D009154:Mutation; D010748:Phosphopeptides / Q000737:chemistry*; D010766:Phosphorylation; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D013379:Substrate Specificity; D013844:Thiazoles / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: C577852:2-(2-(trifluoromethoxy)benzamido)-N-(6-(trifluoromethyl)-1H-benzo(d)imidazol-2-yl)thiazole-4-carboxamide; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D010748:Phosphopeptides; D011994:Recombinant Proteins; D013844:Thiazoles; D048149:Casein Kinase 1 epsilon; D048148:Casein Kinase Idelta