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Molecules. 2018 Mar 23;23(4). pii: E736. doi: 10.3390/molecules23040736.

Facilitating Anti-Cancer Combinatorial Drug Discovery by Targeting Epistatic Disease Genes.

Author information

1
Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University, Wuhan 430070, China. qyuan@webmail.hzau.edu.cn.
2
Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University, Wuhan 430070, China. liumengyuan2017@outlook.com.
3
Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University, Wuhan 430070, China. lym17@webmail.hzau.edu.cn.
4
Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University, Wuhan 430070, China. zhulinda@hotmail.com.
5
School of Life Sciences, Shandong University of Technology; No. 12 Zhangzhou Road, Zibo 255049, China. wuyushanna@126.com.
6
Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University, Wuhan 430070, China. luozhihui@simm.ac.cn.
7
School of Life Sciences, Shandong University of Technology; No. 12 Zhangzhou Road, Zibo 255049, China. sleevexz@sdut.edu.cn.
8
Department of Botany and Plant Sciences, University of California, Riverside, CA 92521, USA. shizhong.xu@ucr.edu.
9
Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University, Wuhan 430070, China. yqy@mail.hzau.edu.cn.
10
Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University, Wuhan 430070, China. zhy630@mail.hzau.edu.cn.

Abstract

Due to synergistic effects, combinatorial drugs are widely used for treating complex diseases. However, combining drugs and making them synergetic remains a challenge. Genetic disease genes are considered a promising source of drug targets with important implications for navigating the drug space. Most diseases are not caused by a single pathogenic factor, but by multiple disease genes, in particular, interacting disease genes. Thus, it is reasonable to consider that targeting epistatic disease genes may enhance the therapeutic effects of combinatorial drugs. In this study, synthetic lethality gene pairs of tumors, similar to epistatic disease genes, were first targeted by combinatorial drugs, resulting in the enrichment of the combinatorial drugs with cancer treatment, which verified our hypothesis. Then, conventional epistasis detection software was used to identify epistatic disease genes from the genome wide association studies (GWAS) dataset. Furthermore, combinatorial drugs were predicted by targeting these epistatic disease genes, and five combinations were proven to have synergistic anti-cancer effects on MCF-7 cells through cell cytotoxicity assay. Combined with the three-dimensional (3D) genome-based method, the epistatic disease genes were filtered and were more closely related to disease. By targeting the filtered gene pairs, the efficiency of combinatorial drug discovery has been further improved.

KEYWORDS:

3D genome; GWAS; combinatorial drug; drug target; epistasis

PMID:
29570606
PMCID:
PMC6017788
DOI:
10.3390/molecules23040736
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

We have received research/grant support from Wuhan Bio-Links Technology Co., Ltd. Huazhong Agricultural University and the developers of the methods for drug discovery and drug repositioning may benefit financially pursuant to the University’s Policy on Inventions, Patents and Technology Transfer, even if these methods are not used in the commercialized therapy.

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