4TW9: Difluoro-dioxolo-benzoimidazol-benzamides As Potent Inhibitors Of Ck1delta And Epsilon With Nanomolar Inhibitory Activity On Cancer Cell Proliferation

Citation:
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 CK1delta/epsilon-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 CK1delta. 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 CK1delta-specific small molecule inhibitors with increased biological activity.
PDB ID: 4TW9Download
MMDB ID: 122021
PDB Deposition Date: 2014/6/30
Updated in MMDB: 2014/10
Experimental Method:
x-ray diffraction
Resolution: 2.4  Å
Source Organism:
Similar Structures:
Biological Unit for 4TW9: dimeric; determined by author and by software (PISA)
Molecular Components in 4TW9
Label Count Molecule
Proteins (2 molecules)
2
Casein Kinase I Isoform Delta(Gene symbol: CSNK1D)
Molecule annotation
Chemicals (18 molecules)
1
8
2
2
3
2
4
4
5
2
* Click molecule labels to explore molecular sequence information.

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