Thread by @metapredict

1/ Our contribution to drug repositioning (DR) for metabolic disease (MD)
In HUMANS Insulin resistance (IR) in muscle & adipose shares COMMON molecular pathways & COMMON treatment responses (n= >2,000 samples). @mackinprof @eLIFE @JPTK_TechBio @chvolmar
doi.org/10.7554/eLife.…

2/ Using the common molecular features from muscle & adipose we built a 120-gene RNA IR assay & found this multi-gene assay could rank families of active drugs by potency #novel Active drugs have many protein targets #not-novel
@mackinprof @eLIFE
doi.org/10.7554/eLife.…

3/ The assay identified >200 +ve & -ve acting drugs – many proven to improve or impair insulin signalling. Not all +ve drugs will be safe to explore further but many had efficacy in recent MD models @mackinprof @eLIFE
doi.org/10.7554/eLife.…

4) #DeepLearning models helped explore kinase inhibitor specificity and compensate for lack of in vitro potency data, when exploring mechanism of action and off-target activities
@mackinprof @eLIFE @JPTK_TechBio
doi.org/10.7554/eLife.…

5) The assay selected a range of inhibitors e.g. glucosylceramide synthase @StephenORahilly 2007, and Nifedipine Sheu 1991, Visfatin Lockman 2010 & many that emerged & cited during our project. Old Science & Replication is GRRRRREAT.
@mackinprof @eLIFE
doi.org/10.7554/eLife.…

6/ The 120-gene assay allowed us to link active drug targets to disease pathways. Notably protein targets of active drugs connect at PATHWAY level, but they are NOT usually the differentially regulated gene biomarkers #Novel #Repurpose
@mackinprof @eLIFE
doi.org/10.7554/eLife.…

7) Information from the dual-tissue exercise-treatment signature improved the performance of fasting disease signature alone #L1000
MD GWAS derived gene lists were NOT useful at all in this DR project
@mackinprof @eLIFE @chvolmar
doi.org/10.7554/eLife.…

8/ Are the drugs mimicking ‘exercise’? Not ‘exercise in a pill’ – but they may have potential to enhance some responses to exercise
Notably +ve drugs seem to target PROXIMAL aspects of insulin signalling not distal targets
@mackinprof @eLIFE
doi.org/10.7554/eLife.…

9) This assay is for drugs that reverse HOMA2-IR; other aspects of insulin sig to be incorporated + need to better understand nuclear receptor activity in assay in vitro setting
@mackinprof @eLIFE
doi.org/10.7554/eLife.…

10) QED - Bulk transcriptomics can define metabolic disease & design IR drug repositioning assays. Unlike Aussie mice, human adipose & muscle share COMMON IR pathways & treatment responses, including proteins causally regulating IR
@mackinprof @eLIFE
doi.org/10.7554/eLife.…