A human-based multi-gene signature enables quantitative drug repurposing for metabolic disease.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Timmons, JA; Anighoro, A; Brogan, RJ; Stahl, J; Wahlestedt, C; Farquhar, DG; Taylor-King, J; Volmar, C-H; Kraus, WE; Phillips, SM

Published Date

  • January 17, 2022

Published In

Volume / Issue

  • 11 /

PubMed ID

  • 35037854

Pubmed Central ID

  • PMC8763401

Electronic International Standard Serial Number (EISSN)

  • 2050-084X

Digital Object Identifier (DOI)

  • 10.7554/eLife.68832

Language

  • eng

Conference Location

  • England