title: FUSION-Guided Hypothesis Development Leads to the Identification of N⁶,N⁶-Dimethyladenosine, a Marine-Derived AKT Pathway Inhibitor.
abstract: 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.
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA. Rachel.Vaden2@UTSouthwestern.edu.
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Vaden
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA. Nathaniel.Oswald@UTSouthwestern.edu.
authors.forename: Nathaniel W
authors.initials: NW
authors.lastname: Oswald
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA. Malia.Potts@StJude.org.|Cell & Molecular Biology Department, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Malia.Potts@StJude.org.
authors.forename: Malia B
authors.initials: MB
authors.lastname: Potts
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA. John.MacMillan@UTSouthwestern.edu.
authors.forename: John B
authors.initials: JB
authors.lastname: MacMillan
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA. Michael.White@UTSouthwestern.edu.
authors.forename: Michael A
authors.initials: MA
authors.lastname: White
mesh_terms: D059001:Aquatic Organisms / Q000737:chemistry*; D001419:Bacteria / Q000737:chemistry*; D064229:Biological Ontologies; D001688:Biological Products / Q000737:chemistry* / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D045744:Cell Line, Tumor; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D001688:Biological Products; D051057:Proto-Oncogene Proteins c-akt
keywords: AKT; dimethyladenosine; functional signature ontology