Differential mechanism of action of the CK1ε inhibitor GSD0054

Abstract

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.

Synthesis and in vitro study of antiproliferative benzyloxy dihydropyrimidinones

“…and T-47D (breast), HeLa (cervix), and WiDr (colon). We followed our implementation of the NCI protocol [20] and used the standard anticancer drug cisplatin (CDDP) as a reference compound. The results of the assay given in GI 50 (molar concentration of the compound that inhibits 50% net cell growth) are shown in Table 3.…”

Structure-Based Development of Isoform-Selective Inhibitors of Casein Kinase 1ε vs Casein Kinase 1δ

“…Recently, a sphingosine analogue, GSD0054, was identified as a highly selective CK1ε inhibitor with antiproliferative activity from the phenotypic screening of a small library of enantiopure anti-β-amino alcohols and KINOME profiling assay. 19,20 However, its IC 50 values and modes of inhibition in the target enzyme were not reported. In addition, the high selectivity of GSD0054 to CK1ε has not been clearly understood.…”

“…Several highly potent and CK1-selective inhibitors have been developed, , and some have been used to characterize the pharmacological effects of CK1 inhibition in animal models. ,, However, most of these agents are ATP-competitive type I inhibitors, and most lack specificity for individual CK1 isoforms. Recently, a sphingosine analogue, GSD0054, was identified as a highly selective CK1ε inhibitor with antiproliferative activity from the phenotypic screening of a small library of enantiopure anti -β-amino alcohols and KINOME profiling assay. , However, its IC 50 values and modes of inhibition in the target enzyme were not reported. In addition, the high selectivity of GSD0054 to CK1ε has not been clearly understood.…”