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

    ROR https://ror.org/01r9z8p25

  2. 2 Universidade da Madeira
    info

    Universidade da Madeira

    Funchal, Portugal

    ROR https://ror.org/0442zbe52

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

ISSN: 2616-3632,  2617-5282

Año de publicación: 2018

Volumen: 1

Número: 2

Páginas: 77-83

Tipo: Artículo

DOI: 10.31083/J.JMCM.2018.02.004 GOOGLE SCHOLAR lock_openAcceso abierto editor

Otras publicaciones en: Journal of Molecular and Clinical Medicine

Objetivos de desarrollo sostenible

Resumen

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

Referencias bibliográficas

  • Vielhaber E, Virshup DM. Casein kinase I: from obscurity to centerstage.IUBMB Life, 2001; 51: 73-78
  • Knippschild U, Wolff S, Giamas G, Brockschmidt C, Wittau M, W ̈urlPU, Eismann T, St ̈oter M. The role of the casein kinase 1 (CK1) familyin different signaling pathways linked to cancer development.Onkologie,2005; 28: 508-514
  • Knippschild U, Kr ̈uger M, Richter J, Xu P, Garc ́ıa-Reyes B, PeiferC, Halekotte J, Bakulev V, Bischof J. The CK1 family: contributionto cellular stress response and its role in carcinogenesis.Front Oncol,2014; 4: 96
  • Yang WS, Stockwell BR. Inhibition of casein kinase 1-epsilon inducescancer-cell-selective, PERIOD2-dependent growth arrest.Genome Biol, 2008; 9: R92
  • Price MA. CK1, there’s more than one: casein kinase I family membersin Wnt and Hedgehog signalling. Genes Dev, 2006; 20: 399-410
  • Kim SY, Dunn IF, Firestein R, Gupta P, Wardwell L, Repich K, SchinzelAC, Wittner B, Silver SJ, Root DE, Boehm JS, Ramaswamy S, LanderES, Hahn WC. CK1εis required for breast cancers dependent onβ-catenin activity.PLoS One, 2010; 5: e8979
  • Cheong JK, Nguyen TH, Wang H, Tan P, Voorhoeve PM, Lee SH,Virshup DM. IC261 induces cell cycle arrest and apoptosis of humancancer cells via CK1δ/εand Wnt/β-catenin independent inhibition ofmitotic spindle formation.Oncogene, 2011; 30: 2558-2569.
  • Silveira-Dorta G, Sousa IJ, Fernandes MX, Martín VS, Padrón JM.Synthesis and identification of unprecedented selective inhibitors ofCK1ε.Eur J Med Chem, 2015; 96: 308-317
  • Silveira-Dorta G, Donadel OJ, Martín VS, Padr ́on JM. Direct stereose-lective synthesis of enantiomerically pureanti-β-amino alcohols.J OrgChem, 2014; 79: 6775-6782
  • Monks A, Scudiero D, Skehan P, Shoemaker R, Paull K, Vistica D, HoseC, Langley J, Cronise P, Vaigro-Wolff A, Gray-Goodrich M, CampbellH, Mayo J, Boyd M. Feasibility of a high-flux anticancer drug screenusing a diverse panel of cultured human tumor cell lines.J Natl CancerInst, 1991; 83: 757-766
  • Gilson MK, Liu T, Baitaluk M, Nicola G, Hwang L, Chong J. Bind-ingDB in 2015: A public database for medicinal chemistry, computa-tional chemistry and systems pharmacology.Nucleic Acids Res, 2016;44: D0145-D1053
  • Bradley G, Juranka PF, Ling V. Mechanism of multidrug resistance.Biochim Biophys Acta, 1988; 948: 87-128
  • Rodriguez N, Yang J, Hasselblatt K, Liu S, Zhou Y, Rauh-Hain JA, NgSK, Choi PW, Fong WP, Agar NY, Welch WR, Berkowitz RS, Ng SW.Casein kinase 1 epsilon interacts with mitochondrial proteins for thegrowth and survival of human ovarian cancer cells.EMBO Mol Med,2012; 4: 952-963
  • Behrend L, Milne DM, St ̈oter M, Deppert W, Campbell LE, Meek DW,Knippschild U. IC261, a specific inhibitor of the protein kinases caseinkinase 1-delta and -epsilon, triggers the mitotic checkpoint and inducesp53-dependent postmitotic effects.Oncogene, 2000; 19: 5303-5313
  • Hao J, Ao A, Zhou L, Murphy CK, Frist AY, Keel JJ, Thorne CA,Kim K, Lee E, Hong CC. Selective small molecule targetingβ-cateninfunction discovered by in vivo chemical genetic screen.Cell Rep, 2013; 4: 898-904