Theranostics 2018; 8(13):3504-3516. doi:10.7150/thno.24336

Research Paper

Comparative profiling of analog targets: a case study on resveratrol for mouse melanoma metastasis suppression

Xiao Chen1, Wei Li1, Chengchao Xu2, Jie Wang1, Bo Zhu1, Qilai Huang1, Dianhua Chen1, Jianfei Sheng3, Yong Zou3, Yew Mun Lee2, Renxiang Tan1, Pingping Shen1, Yin Kwan Wong2, Qingsong Lin2, Jigang Wang4,5,2,✉, Zichun Hua1,✉

1. The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China
2. Department of Biological Science, National University of Singapore, Singapore, 117543, Singapore
3. School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China
4. Artemisinin Research Center, China Academy of Chinese Medical Sciences, Beijing, 100700, China
5. Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China


Many plant-specialized metabolites have remedial properties and provide an endless chemical resource for drug discovery. However, most of these metabolites have promiscuous binding targets in mammalian cells and elicit a series of responses that collectively change the physiology of the cells. To explore the potential of these multi-functional and multi-targeted drugs, it is critical to understand the direct relationships between their key chemical features, the corresponding binding targets and the relevant biological effects, which is a prerequisite for future drug modification and optimization.

Methods: We introduced and demonstrated a general workflow, called Comparative Profiling of Analog Targets (CPAT), to connect specific biological effects with defined chemical structures of drugs. Using resveratrol (RSV) as an example, we have synthesized and characterized a series of partial functional analogs of RSV. An analog (named RSVN) that specifically lost the inhibitory effect of RSV in cell migration was identified. The binding targets of RSVN and RSV was profiled and compared.

Results: Comparative profiling of the RSV and RSVN binding targets showed that, unlike RSV, RSVN failed to target specific components involved in DNA methylation (histone deacetylase 1 [HDAC1] and DNA methyltransferase 3 alpha [DNMT3a]), suggesting that RSV suppresses cell migration through epigenetic regulation. Indeed, RSV treatment recruited HDAC1 and DNMT3a to the promoter region of the focal adhesion kinase (FAK), a key factor involved in cell adhesion, enhanced the promoter methylation, and thus attenuated the protein expression. The inhibitory effect of RSV in cell migration was diminished once FAK expression was restored. Thus, the mechanism of RSV in inhibiting cell migration could be largely accounted to epigenetically control of FAK expression.

Conclusion: Our results showed that even though RSV exhibits promiscuous binding, its inhibitory effect on cell migration can be mechanistically understood. First, the presence of 4'-hydroxystilbene within the RSV structure is essential for this activity. Second, it inhibits cell migration through epigenetically based downregulation of FAK expression. Taken together, we propose that CPAT might also be adapted to delineate the specific function of other natural products (NPs) that exhibit binding promiscuity.

Keywords: CPAT, resveratrol, target identification, chemical proteomics, cancer metastasis.

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How to cite this article:
Chen X, Li W, Xu C, Wang J, Zhu B, Huang Q, Chen D, Sheng J, Zou Y, Lee YM, Tan R, Shen P, Wong YK, Lin Q, Wang J, Hua Z. Comparative profiling of analog targets: a case study on resveratrol for mouse melanoma metastasis suppression. Theranostics 2018; 8(13):3504-3516. doi:10.7150/thno.24336. Available from