FUSION-Guided Hypothesis Development Leads to the Identification of N6,N6-Dimethyladenosine, a Marine-Derived AKT Pathway InhibitorReportar como inadecuado


FUSION-Guided Hypothesis Development Leads to the Identification of N6,N6-Dimethyladenosine, a Marine-Derived AKT Pathway Inhibitor


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1

Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA

2

Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA

3

Cell and Molecular Biology Department, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA





*

Authors to whom correspondence should be addressed.



Academic Editors: Yu-Dong Zhou, Dale G. Nagle and Paul Long

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. View Full-Text

Keywords: dimethyladenosine; AKT; functional signature ontology dimethyladenosine; AKT; functional signature ontology





Autor: Rachel M. Vaden 1, Nathaniel W. Oswald 2, Malia B. Potts 1,3, John B. MacMillan 2,* and Michael A. White 1,*

Fuente: http://mdpi.com/



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