Differential mechanism of action of the CK1ε inhibitor GSD0054

• Autor(a) principal: Lagunes, Irene
• Data de Publicação: 2018
• Outros Autores: Martín-Batista, Elva, Silveira-Dorta, Gaston, Fernandes, Miguel X., Padrón, Jose M.
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10400.13/5030
• topic: Synthetic lethality; Casein kinase inhibitors; Wnt/beta-catenin; Anti-beta-amino alcohols; Breast cancer; .; Faculdade de Ciências Exatas e da Engenharia

In the current study, we explored for the first time, the mechanism of action of the new Casein kinase 1 ε (CK1ε) selective inhibitor GSD0054. Although GSD0054 behaved as a selective CK1ε inhibitor in enzymatic assays, we studied whether this inhibitory activity also occurred inside the cells. The effects of GSD0054 on β-catenin expression and disruption of cell cycle progression were studied in the human breast cancer cell lines MDA-MB-453 (β-catenin negative) and T-47D (β-catenin positive). We also performed molecular modeling studies using computational docking against CK1ε to explain and predict the mechanism of action of this compound. Moreover, the commercially available CK1ε inhibitor PF-4800567 and the CK1δ/ε inhibitors PF-670462 and IC261 were also studied for comparison purposes. GSD0054 showed anti-proliferative activity against MDA-MB-453 and T-47D cells despite the fact that MDA-MB-453 cells do not possess active β-catenin. However, selective cell killing occurred in the more resistant, β-catenin active, T-47D cells. CK1ε was confirmed as a cellular target, although other targets or alternative mechanisms of action could possibly explain the anti-proliferative activity in MDA-MB-453 cells.