FUSION-Guided Hypothesis Development Leads to the Identification of N6,N6-Dimethyladenosine, a Marine-Derived AKT Pathway Inhibitor
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 harness...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2017-03-01
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| Series: | Marine Drugs |
| Subjects: | |
| Online Access: | http://www.mdpi.com/1660-3397/15/3/75 |
| _version_ | 1797999928573689856 |
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| author | Rachel M. Vaden Nathaniel W. Oswald Malia B. Potts John B. MacMillan Michael A. White |
| author_facet | Rachel M. Vaden Nathaniel W. Oswald Malia B. Potts John B. MacMillan Michael A. White |
| author_sort | Rachel M. Vaden |
| collection | DOAJ |
| description | 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, N6,N6-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. |
| first_indexed | 2024-04-11T11:12:24Z |
| format | Article |
| id | doaj.art-f4f5598e9eed4b1e82f6d6c4ced51029 |
| institution | Directory Open Access Journal |
| issn | 1660-3397 |
| language | English |
| last_indexed | 2024-04-11T11:12:24Z |
| publishDate | 2017-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Marine Drugs |
| spelling | doaj.art-f4f5598e9eed4b1e82f6d6c4ced510292022-12-22T04:27:26ZengMDPI AGMarine Drugs1660-33972017-03-011537510.3390/md15030075md15030075FUSION-Guided Hypothesis Development Leads to the Identification of N6,N6-Dimethyladenosine, a Marine-Derived AKT Pathway InhibitorRachel M. Vaden0Nathaniel W. Oswald1Malia B. Potts2John B. MacMillan3Michael A. White4Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75235, USADepartment of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75235, USADepartment of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75235, USADepartment of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75235, USADepartment of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75235, USAChemicals 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, N6,N6-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.http://www.mdpi.com/1660-3397/15/3/75dimethyladenosineAKTfunctional signature ontology |
| spellingShingle | Rachel M. Vaden Nathaniel W. Oswald Malia B. Potts John B. MacMillan Michael A. White FUSION-Guided Hypothesis Development Leads to the Identification of N6,N6-Dimethyladenosine, a Marine-Derived AKT Pathway Inhibitor Marine Drugs dimethyladenosine AKT functional signature ontology |
| title | FUSION-Guided Hypothesis Development Leads to the Identification of N6,N6-Dimethyladenosine, a Marine-Derived AKT Pathway Inhibitor |
| title_full | FUSION-Guided Hypothesis Development Leads to the Identification of N6,N6-Dimethyladenosine, a Marine-Derived AKT Pathway Inhibitor |
| title_fullStr | FUSION-Guided Hypothesis Development Leads to the Identification of N6,N6-Dimethyladenosine, a Marine-Derived AKT Pathway Inhibitor |
| title_full_unstemmed | FUSION-Guided Hypothesis Development Leads to the Identification of N6,N6-Dimethyladenosine, a Marine-Derived AKT Pathway Inhibitor |
| title_short | FUSION-Guided Hypothesis Development Leads to the Identification of N6,N6-Dimethyladenosine, a Marine-Derived AKT Pathway Inhibitor |
| title_sort | fusion guided hypothesis development leads to the identification of n6 n6 dimethyladenosine a marine derived akt pathway inhibitor |
| topic | dimethyladenosine AKT functional signature ontology |
| url | http://www.mdpi.com/1660-3397/15/3/75 |
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