4TW9

Difluoro-dioxolo-benzoimidazol-benzamides as potent inhibitors of CK1delta and epsilon with nanomolar inhibitory activity on cancer cell proliferation

Summary for 4TW9

• Entry DOI: 10.2210/pdb4tw9/pdb
• Descriptor: Casein kinase I isoform delta, SULFATE ION, octyl beta-L-talopyranoside, ... (7 entities in total)
• Functional Keywords: transferase, ck1delta, ck1epsilon, phosphorylation, small molecule inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 71192.10

Authors

Richter, J.,Bischof, J.,Zaja, M.,Kohlhof, H.,Othersen, O.,Vitt, D.,Alscher, V.,Pospiech, I.,Garcia-Reyes, B.,Berg, S.,Leban, J.,Knippschild, U. (deposition date: 2014-06-30, release date: 2014-07-30, Last modification date: 2024-05-08)

Primary citation

Richter, J.,Bischof, J.,Zaja, M.,Kohlhof, H.,Othersen, O.,Vitt, D.,Alscher, V.,Pospiech, I.,Garcia-Reyes, B.,Berg, S.,Leban, J.,Knippschild, U.
Difluoro-dioxolo-benzoimidazol-benzamides As Potent Inhibitors of CK1 delta and epsilon with Nanomolar Inhibitory Activity on Cancer Cell Proliferation.
J.Med.Chem., 57:7933-7946, 2014

PubMed 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.

PubMed: 25191940
DOI: 10.1021/jm500600b

Experimental method

X-RAY DIFFRACTION (2.4 Å)