Difluoro-dioxolo-benzoimidazol-benzamides As Potent Inhibitors of CK1δ and ε with Nanomolar Inhibitory Activity on Cancer Cell Proliferation

Abstract

Deregulation of CK1 (casein kinase 1) activity can be involved in the development of several pathological disorders and diseases such as cancer. Therefore, research interest in identifying potent CK1-specific inhibitors is still increasing. A previously published potent and selective benzimidazole-derived CK1δ/ε-specific inhibitor compound with significant effects on several tumor cell lines was further modified to difluoro-dioxolo-benzoimidazole derivatives displaying remarkable inhibitory effects and increased intracellular availability. In the present study, we identified two heterocyclic molecules as new CK1-specific inhibitor compounds with favorable physicochemical properties and notable selectivity in a kinome-wide screen. Being compared to other CK1 isoforms, these compounds exhibited advanced isoform selectivity toward CK1δ. Moreover, newly designed compounds showed increased growth inhibitory activity in a panel of different tumor cell lines as determined by analyses of cell viability and cell cycle distribution. In summary, presented lead optimization resulted in new highly selective CK1δ-specific small molecule inhibitors with increased biological activity.

Effects of altered expression and activity levels of CK1δ and ɛ on tumor growth and survival of colorectal cancer patients

“…In the present work we detected differences in the expression levels and activity of CK1α, δ and ɛ in colon cancer cell lines SW620, SW480 and HT29. Furthermore, we could show that growth rates of all three colon tumor cell lines were significantly reduced in the presence of the CK1δ/ɛ‐specific inhibitors IC261, compound 1 , and compound 2 . The two novel CK1δ‐specific inhibitors 1 and 2 which are related to previously published CK1δ and ɛ selective benzimidazole derivatives strongly inhibited the growth of all three colon tumor cell lines.…”

“…Furthermore, we could show that growth rates of all three colon tumor cell lines were significantly reduced in the presence of the CK1d/E-specific inhibitors IC261, compound 1, and compound 2. 25 The two novel CK1d-specific inhibitors 1 and 2 which are related to previously published CK1d and E selective benzimidazole derivatives 13 strongly inhibited the growth of all three colon tumor cell lines. Furthermore, cell viability and cell cycle distribution in a cell line and dose-dependent manner were affected pointing to an essential role for CK1d in cancer cell proliferation.…”

Targeting Protein Kinase CK1δ with Riluzole: Could It Be One of the Possible Missing Bricks to Interpret Its Effect in the Treatment of ALS from a Molecular Point of View?

“…Curiously,t hree ATP-competitivei nhibitors belong to the benzothiazole and benzimidazole families:inp articular,ass hown in Figure2,the compound 9XK (PDB ID:5 OKT) is a2 -aminobenzothiazole, whereas compounds 37J (PDB ID:4 TWC)a nd 386 (PDB ID:4 TW9) are 2-aminobenzimidazoles. [16][17][18] Looking at the ATP-binding site, both benzothiazole and benzimidazole scaffolds are anchored to the hinge region of the protein kinase throughaconserved hydrogen bond network, similar to what wasa lso observed for the ATPb inding mode. Furthermore, the benzothiazole scaffold has been extensivelyi nvestigateda sas tartingp oint for computer-aided designa nd for the subsequents ynthesis of potent CK1d inhibitors, for which structural data are not available.…”

“…Our computational work started with a conventional visual inspection of all co‐crystallized ligands followed by scaffold clustering based on different similarity metrics such as MACCS‐driven Tanimoto and Dice indexes. Curiously, three ATP‐competitive inhibitors belong to the benzothiazole and benzimidazole families: in particular, as shown in Figure , the compound 9XK (PDB ID: https://www.rcsb.org/structure/5OKT) is a 2‐aminobenzothiazole, whereas compounds 37J (PDB ID: https://www.rcsb.org/structure/4TWC) and 386 (PDB ID: https://www.rcsb.org/structure/4TW9) are 2‐aminobenzimidazoles . Looking at the ATP‐binding site, both benzothiazole and benzimidazole scaffolds are anchored to the hinge region of the protein kinase through a conserved hydrogen bond network, similar to what was also observed for the ATP binding mode.…”

Design and synthesis of N-benzimidazol-2-yl-N'-sulfonyl acetamidines

“…In vitro kinase assays were performed with different CK1 isoforms and selected compounds at an ATP concentration of 10 µM and using DMSO controls as described previously. 32,33 Bovine GST-CK1α (FP296) 34 human GST-CK1γ (FP1054) 35 human GST-CK1δ TV1 (FP1417), 36 and recombinant human GST-CK1ε (FP455) 37 were used as sources of enzyme. Phosphorylated proteins were separated by SDS-PAGE and stained with Coomassie.…”