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

Amino Acids
Joachim BischofUwe Knippschild

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.

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Citations

Jul 19, 2013·PloS One·Joachim BischofUwe Knippschild
Jan 11, 2014·Neurochemical Research·Letizia MarvaldiLars Klimaschewski
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Feb 26, 2016·European Journal of Medicinal Chemistry·Sahil SharmaKunal Nepali
Oct 16, 2015·Amino Acids·Chiara IanesUwe Knippschild
Jan 16, 2016·European Journal of Medicinal Chemistry·Debasis DasMoumita Bairagi
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Mar 10, 2015·Frontiers in Cell and Developmental Biology·B Sophia WinklerUwe Knippschild
Jun 7, 2014·Frontiers in Oncology·Uwe KnippschildJoachim Bischof
Mar 25, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Jakob HalekotteChristian Peifer
Mar 6, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Andreas LuxenburgerChristian Peifer
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Aug 28, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Aileen RothJoachim Bischof

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Methods Mentioned

BETA
column chromatography
PCR
X-ray
FCS
electrophoresis

Software Mentioned

DISCOVERX
CellQuest
MOE MOE Molecular Operating Environment
MOE
KINOME
TREE spot [UNK] Software Tool

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