A human-based multi-gene signature enables quantitative drug repurposing for metabolic disease Journal Articles uri icon

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  • Insulin resistance (IR) contributes to the pathophysiology of diabetes, dementia, viral infection, and cardiovascular disease. Drug repurposing (DR) may identify treatments for IR; however, barriers include uncertainty whether in vitro transcriptomic assays yield quantitative pharmacological data, or how to optimise assay design to best reflect in vivo human disease. We developed a clinical-based human tissue IR signature by combining lifestyle-mediated treatment responses (>500 human adipose and muscle biopsies) with biomarkers of disease status (fasting IR from >1200 biopsies). The assay identified a chemically diverse set of >130 positively acting compounds, highly enriched in true positives, that targeted 73 proteins regulating IR pathways. Our multi-gene RNA assay score reflected the quantitative pharmacological properties of a set of epidermal growth factor receptor-related tyrosine kinase inhibitors, providing insight into drug target specificity; an observation supported by deep learning-based genome-wide predicted pharmacology. Several drugs identified are suitable for evaluation in patients, particularly those with either acute or severe chronic IR.


  • Timmons, James A
  • Anighoro, Andrew
  • Brogan, Robert J
  • Stahl, Jack
  • Wahlestedt, Claes
  • Farquhar, David Gordon
  • Taylor-King, Jake
  • Volmar, Claude-Henry
  • Kraus, William E
  • Phillips, Stuart

publication date

  • January 17, 2022

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