Facts and myths of selective casein kinase 1ε einhibition

Resumo

In the scenario of drug discovery, the challenge is to fully understand and elucidate the mechanism of action to identify, withhigh resolution, the molecular determinant(s) targeted by the drug and responsible for its pharmacological activity. Cancer offersscientists an almost infinite arena of signaling pathways, targets and small molecules for therapeutic intervention. Among themultiple chemotherapeutic strategies to combat cancer, synthetic lethality remains underexplored. Casein kinase 1 ε (CK1ε) isa 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 lethalpartner and its inhibitors as chemotherapeutics: the therapeutic relevance of this kinase, the scarce availability of selectiveinhibitors (due to the high homology with its sibling isoform CK1δ ), and the constraint of existing computational tools. This paperrepresents the first review covering the potential of CK1ε as a druggable target for cancer treatment.