期刊
MARINE DRUGS
卷 15, 期 3, 页码 -出版社
MDPI AG
DOI: 10.3390/md15030075
关键词
dimethyladenosine; AKT; functional signature ontology
资金
- Welch Foundation [I-1414, I-1689]
- US National Cancer Institute [R35CA197717, CA176284, CA149833]
- Cancer Prevention and Research Institute of Texas [RP120718, RP110708]
- NIH Center for Complementary and Integrative Health
- NIH Office of Dietary Supplements [U41 AT008718]
Chemicals found in nature have evolved over geological time scales to productively interact with biological molecules, and thus represent an effective resource for pharmaceutical development. Marine-derived bacteria are rich sources of chemically diverse, bioactive secondary metabolites, but harnessing this diversity for biomedical benefit is limited by challenges associated with natural product purification and determination of biochemical mechanism. Using Functional Signature Ontology (FUSION), we report the parallel isolation and characterization of a marine-derived natural product, N-6,N-6-dimethyladenosine, that robustly inhibits AKT signaling in a variety of non-small cell lung cancer cell lines. Upon validation of the elucidated structure by comparison with a commercially available sample, experiments were initiated to understand the small molecule's breadth of effect in a biological setting. One such experiment, a reverse phase protein array (RPPA) analysis of >50 kinases, indicated a specific cellular response to treatment. In all, leveraging the FUSION platform allowed for the rapid generation and validation of a biological mechanism of action hypothesis for an unknown natural product and permitted accelerated purification of the bioactive component from a chemically complex fraction.
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