Targeting CK1 isoforms in colon and rectal cancer: Initial steps towards the development of CK1 mutant-specific inhibitors

Colon and rectal cancer (CRC) represents the fourth leading cause of cancer related deaths among all neoplastic diseases. Dysregulation of expression and/or kinase activity of CK1 isoforms can be linked to tumorigenesis and oncogenic mutations in CK1 have previously been found in CRC patients. Therefore, inhibition of overexpressed or mutated CK1 isoforms is supposed to have promising potential for the treatment of CRC. In order to detect further hyperactive and potentially oncogenic CK1 mutants we first analyzed the kinetic properties of several CK1δ mutants, which have been reported in different tumor entities. In subsequent experiments, we aimed at identifying small molecule inhibitors able to inhibit wild type and CK1δ mutants and to affect the growth of established (tumor) cell lines either expressing wild type or mutant CK1δ. In addition to well-established inhibitors of CK1 also newly developed compounds were tested, which are based on previously characterized IWP compounds (“inhibitors of Wnt production”). Among the tested molecules, inhibitors demonstrating CK1 isoform-specific as well as mutant-specific effects could be detected. Therefore, our results represent a starting point for further optimization approaches in the development of highly effective and specific CK1-targeting small molecule inhibitors.