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Open AccessArticle

Newly Developed CK1-Specific Inhibitors Show Specifically Stronger Effects on CK1 Mutants and Colon Cancer Cell Lines

1
Department of General and Visceral Surgery, Ulm University Hospital, Albert-Einstein-Allee 23, 89081 Ulm, Germany
2
Institute of Pharmacy, Christian-Albrechts-University of Kiel, Gutenbergstraße 76, 24118 Kiel, Germany
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2019, 20(24), 6184; https://doi.org/10.3390/ijms20246184
Received: 30 October 2019 / Revised: 29 November 2019 / Accepted: 5 December 2019 / Published: 7 December 2019
(This article belongs to the Special Issue Molecular and Translational Research on Colorectal Cancer)
Protein kinases of the CK1 family can be involved in numerous physiological and pathophysiological processes. Dysregulated expression and/or activity as well as mutation of CK1 isoforms have previously been linked to tumorigenesis. Among all neoplastic diseases, colon and rectal cancer (CRC) represent the fourth leading cause of cancer related deaths. Since mutations in CK1δ previously found in CRC patients exhibited increased oncogenic features, inhibition of CK1δ is supposed to have promising therapeutic potential for tumors, which present overexpression or mutations of this CK1 isoform. Therefore, it is important to develop new small molecule inhibitors exhibiting higher affinity toward CK1δ mutants. In the present study, we first characterized the kinetic properties of CK1δ mutants, which were detected in different tumor entities. Subsequently, we characterized the ability of several newly developed IWP-based inhibitors to inhibit wild type and CK1δ mutants and we furthermore analyzed their effects on growth inhibition of various cultured colon cancer cell lines. Our results indicate, that these compounds represent a promising base for the development of novel CRC therapy concepts. View Full-Text
Keywords: CK1; small molecule inhibitors; Michaelis–Menten kinetics; casein kinase 1; kinase mutant CK1; small molecule inhibitors; Michaelis–Menten kinetics; casein kinase 1; kinase mutant
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Liu, C.; Witt, L.; Ianes, C.; Bischof, J.; Bammert, M.-T.; Baier, J.; Kirschner, S.; Henne-Bruns, D.; Xu, P.; Kornmann, M.; Peifer, C.; Knippschild, U. Newly Developed CK1-Specific Inhibitors Show Specifically Stronger Effects on CK1 Mutants and Colon Cancer Cell Lines. Int. J. Mol. Sci. 2019, 20, 6184.

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