Differential mechanism of action of the CK1ε inhibitor GSD0054

In the current study, we explored for the first time, the mechanism of action of the new Casein kinase 1e(CK1e) selective inhibitorGSD0054. Although GSD0054 behaved as a selective CK1einhibitor in enzymatic assays, we studied whether this inhibitoryactivity also occurred inside the cells. The effects of GSD0054 onβ-catenin expression and disruption of cell cycle progressionwere studied in the human breast cancer cell lines MDA-MB-453 (β-catenin negative) and T-47D (β-catenin positive). We alsoperformed molecular modeling studies using computational docking against CK1eto explain and predict the mechanism ofaction of this compound. Moreover, the commercially available CK1einhibitor PF-4800567 and the CK1δ/einhibitors PF-670462and IC261 were also studied for comparison purposes. GSD0054 showed anti-proliferative activity against MDA-MB-453 andT-47D cells despite the fact that MDA-MB-453 cells do not possess activeβ-catenin. However, selective cell killing occurred inthe more resistant,β-catenin active, T-47D cells. CK1ewas confirmed as a cellular target, although other targets or alternativemechanisms of action could possibly explain the anti-proliferative activity in MDA-MB-453 cells