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Journal of Molecular and Clinical Medicine   2018, Vol. 1 Issue (4): 195-200    DOI: 10.31083/j.jmcm.2018.04.401
Research article | Next articles
Facts and myths of selective casein kinase 1 ε inhibition
Adrián Puerta1, Alexis R. Galán1, Miguel X. Fernandes1, José M. Padrón1, *()
1 BioLab, Instituto Universitario de Bio-Orgánica "Antonio González" (IUBO-AG), Centro de Investigaciones Biomédicas de Canarias (CIBICAN), Universidad de La Laguna, C/ Astrofísico Francisco Sánchez 2, 38206 La Laguna, Spain.
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In the scenario of drug discovery, the challenge is to fully understand and elucidate the mechanism of action to identify, with high resolution, the molecular determinant(s) targeted by the drug and responsible for its pharmacological activity. Cancer offers scientists an almost infinite arena of signaling pathways, targets and small molecules for therapeutic intervention. Among the multiple chemotherapeutic strategies to combat cancer, synthetic lethality remains underexplored. Casein kinase 1 ε (CK1ε) is a serine/threonine protein kinase that has been described as a synthetic lethal partner of the Wnt/β-catenin signaling pathway. Despite its potential as a desirable therapeutic target, only two selective inhibitors are available: PF-4800567 and GSD0054. Until the discovery of GSD0054, CK1ε inhibitors have been considered candidate drugs exclusively in psychopharmacology. In this review, we focus on three key points which we consider essential to define the scope of CK1ε as a synthetic lethal partner and its inhibitors as chemotherapeutics: the therapeutic relevance of this kinase, the scarce availability of selective inhibitors (due to the high homology with its sibling isoform CK1δ ), and the constraint of existing computational tools. This paper represents the first review covering the potential of CK1ε as a druggable target for cancer treatment.

Key words:  Anticancer drugs      casein kinase 1 epsilon      selective inhibitors      synthetic lethality     
Revised:  22 November 2018      Accepted:  23 November 2018      Published:  20 December 2018     
*Corresponding Author(s):  José M. Padrón     E-mail:

Cite this article: 

Adrián Puerta, Alexis R. Galán, Miguel X. Fernandes, José M. Padrón. Facts and myths of selective casein kinase 1 ε inhibition. Journal of Molecular and Clinical Medicine , 2018, 1(4): 195-200.

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Fig. 1.  Targeting synthetic lethal partners of mutated cancer genes specifically kill cancer cells bearing the inactivating mutations but spare normal cells. In the example shown here, pathways A and B are both intact in normal cells, whereas pathway A is defective in cancer cells. Inhibitors targeting pathway A will cause normal cells to survive through pathway B, whilst tumor cells cannot recover and succumb to this drug treatment scheme. In contrast, inhibitor of pathway B had no differential effect on both types of cells.

Fig. 2.  Chemical structure of selective CK1ε inhibitors (ICK1ε), selective CK1δ inhibitors (ICK1δ ), and dual inhibitors (ICK1δ /ε).

Table 1  Selectivity of casein kinase 1 inhibitors
Compound Selectivity Measure CK1ε CK1δ Ref.
GSD0054 ε %Ctrl 27% 93% [35, 36]
PF-4800567 ε IC50 32 nM 711 nM [37]
SR-3029 δ IC50 260 nM 44 nM [38]
LH846 δ IC50 1.3 μM 290 nM [39]
PF-670462 δ /ε IC50 7.7 nM 14 nM [40]
PF-5006739 δ /ε IC50 17 nM 3.9 nM [41]
IC261 δ /ε IC50 0.6-1.4 μM 0.7-1.3 μM [42]
Table 2  Docking scores (kcal/mol) of casein kinase 1 inhibitors against CK1ε (PDB ID: 4HNI) and CK1δ (PDB ID: 3UYT)
Compound CK1ε CK1δ
GSD0054 -20.6 -18.3
PF-4800567 -22.4 -6.7
SR-3029 -23.2 -16.8
LH846 -18.7 -18.1
PF-670462 -16.6 -14.7
PF-5006739 -18.7 -12.4
IC261 -17.3 -10.6
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