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Protein kinase CK2 has emerged as an attractive cancer therapeutic target. Previous studies have highlighted the challenge of optimizing CK2 ATP-competitive inhibitors that have low druggability due to their polycyclic ring scaffolds. Therefore the development of novel inhibitors with non-polycyclic scaffolds emerges as a promising strategy for drug discovery targeting CK2. In this current study, based on the similar predicted binding poses of the linear 2-propenone scaffold of isoliquiritigenin with that of the polycyclic inhibitor CX-4945, a series of 2-propenone derivatives containing an amine-substituted five-membered heterocycle and a benzoic acid were designed, synthesized and evaluated for their in vitro CK2 inhibition and anti-cancer activity. Compound 8b was found to be the most potent CK2 inhibitor (IC50 = 0.6 mu M) with the anti-proliferative activity on HepG2 cancer cells (IC50 = 14 mu M), compared to the activity of isoliquiritigenin (IC50 = 17 mu M and 51 mu M, respectively). Molecular docking was performed to understand the binding modes of the newly designed 2-propenone derivatives with CK2. Compound 8b formed the most favorable network of hydrogen bonds with both the hinge region and positive area. Our results indicate that CK2 derivatives with a linear 2-propenone scaffold are promising candidates for anti-cancer drug discovery. (C) 2019 Elsevier Inc. All rights reserved.
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来源 :
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
ISSN: 0006-291X
年份: 2019
期: 2
卷: 512
页码: 208-212
3 . 1 0 0
JCR@2022
ESI学科: BIOLOGY & BIOCHEMISTRY;
ESI高被引阀值:61
JCR分区:2