Structure-based identification of novel CK2 inhibitors with a linear 2-propenone scaffold as anti-cancer agents

Qi, Xiaoqian1; Zhang, Na1; Zhao, Lijiao1; Hu, Liming1; Cortopassi, Wilian A.2; Jacobson, Matthew P.2; Li, Xitao3; Zhong, Rugang1

2019-04-30

10.1016/j.bbrc.2019.03.016

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   影响因子和分区

0006-291X

1090-2104

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.

Protein kinase CK2 Structure-based inhibitor design Linear 2-propenone scaffold Anti-cancer activity

SCI

英语

其他

Beijing Municipal Commission of Education Research Projects[KM201610005031]

Biochemistry & Molecular Biology ; Biophysics

Biochemistry & Molecular Biology ; Biophysics

WOS:000468254400011

ACADEMIC PRESS INC ELSEVIER SCIENCE

BIOLOGY & BIOCHEMISTRY

Web of Science

1.Beijing Univ Technol, Coll Life Sci & Bioengn, Beijing Key Lab Environm & Viral Oncol, Beijing 100124, Peoples R China
2.Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94143 USA
3.Southern Univ Sci & Technol, Shenzhen Grubbs Inst, Shenzhen 518055, Peoples R China

Qi, Xiaoqian,Zhang, Na,Zhao, Lijiao,et al. Structure-based identification of novel CK2 inhibitors with a linear 2-propenone scaffold as anti-cancer agents[J]. BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS,2019,512(2):208-212.

Qi, Xiaoqian.,Zhang, Na.,Zhao, Lijiao.,Hu, Liming.,Cortopassi, Wilian A..,...&Zhong, Rugang.(2019).Structure-based identification of novel CK2 inhibitors with a linear 2-propenone scaffold as anti-cancer agents.BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS,512(2),208-212.

Qi, Xiaoqian,et al."Structure-based identification of novel CK2 inhibitors with a linear 2-propenone scaffold as anti-cancer agents".BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 512.2(2019):208-212.