Difluoro-dioxolo-benzoimidazol-benzamides As Potent Inhibitors of CK1未 and 蔚 with Nanomolar Inhibitory Activity on Cancer Cell Proliferation
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- 作者：Julia Richter ; Joachim Bischof ; Mirko Zaja ; Hella Kohlhof ; Olaf Othersen ; Daniel Vitt ; Vanessa Alscher ; Irmgard Pospiech ; Balbina Garc铆a-Reyes ; Sebastian Berg ; Johann Leban ; Uwe Knippschild
- 刊名：Journal of Medicinal Chemistry
- 出版年：2014
- 出版时间：October 9, 2014
- 年：2014
- 卷：57
- 期：19
- 页码：7933-7946
- 全文大小：831K
- ISSN：1520-4804
文摘
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 CK1未/蔚-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 CK1未. 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 CK1未-specific small molecule inhibitors with increased biological activity.