Discovery of Inhibitor of Wnt Production 2 (IWP-2) and Related Compounds As Selective ATP-Competitive Inhibitors of Casein Kinase 1 (CK1) δ/ε

Inhibitors
of Wnt production (IWPs) are known antagonists
of the Wnt pathway, targeting the membrane-bound O-acyltransferase
porcupine (Porcn) and thus preventing a crucial Wnt ligand palmitoylation.
Since IWPs show structural similarities to benzimidazole-based
CK1 inhibitors, we hypothesized that IWPs could also
inhibit CK1 isoforms. Molecular modeling revealed a plausible binding
mode of IWP-2 in the ATP binding pocket of CK1δ
which was confirmed by X-ray analysis. In vitro kinase
assays demonstrated IWPs to be ATP-competitive inhibitors
of wtCK1δ. IWPs also strongly inhibited
the gatekeeper mutant M82FCK1δ. When profiled in
a panel of 320 kinases, IWP-2 specifically inhibited
CK1δ. IWP-2 and IWP-4 also inhibited
the viability of various cancer cell lines. By a medicinal chemistry
approach, we developed improved IWP-derived CK1 inhibitors.
Our results suggest that the effects of IWPs are not
limited to Porcn, but also might influence CK1δ/ε-related
pathways.