Differential mechanism of action of the CK1ε inhibitor GSD0054

  1. Elva Martín-Batista 1
  2. José M. Padrón 1
  3. Irene Lagunes 1
  4. Miguel X. Fernandes 2
  5. Gastón Silveira-Dorta 1
  1. 1 Universidad de La Laguna
    info

    Universidad de La Laguna

    San Cristobal de La Laguna, España

    GRID grid.10041.34

  2. 2 University of Madeira
    info

    University of Madeira

    Funchal, Portugal

    GRID grid.26793.39

Journal:
Journal of Molecular and Clinical Medicine
  1. Prof. Yehuda G. Assaraf

ISSN: 2616-3632

Year of publication: 2018

Volume: 1

Issue: 2

Pages: 77-83

Type: Article

Export: RIS
DOI: 10.31083/j.jmcm.2018.02.004 GOOGLE SCHOLAR lock_openOpen access editor

Abstract

In the current study, we explored for the first time, the mechanism of action of the new Casein kinase 1ε(CK1ε) selective inhibitorGSD0054. Although GSD0054 behaved as a selective CK1εinhibitor 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 CK1εto explain and predict the mechanism ofaction of this compound. Moreover, the commercially available CK1εinhibitor PF-4800567 and the CK1δ/εinhibitors 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. CK1εwas confirmed as a cellular target, although other targets or alternativemechanisms of action could possibly explain the anti-proliferative activity in MDA-MB-453 cells

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