New insights for drug repositioning: the integrative approach Lili Mao*, Mai Fujimoto#, Kouichi Hosomi#, Mitsutaka Takada#, Juran Kato*
*GEXVal Inc., 2-26-1, Muraoka-Higashi, Fujisawa, Kanagawa, 251-0012, Japan#Division of Clinical Drug Informatics, School of Pharmacy, Kindai University, Kowakae, Higashi-osaka, Osaka, Japan,
Nosengo, 2016, Nature
Drug repositioning• Agile• De-risk
• Minimize cost
• Maximize the value
• Unbiased• Systematic• Integrative• Comprehensive• Multiplatform• Cost-effective
Integrative approach
An integrative approach using real-world data to identify alternative therapeutic uses of existing drugs
• Demonstrated potential validity of the integrative approach• Identified the inverse association between IBD and psycholeptics as drug repositioning signal• The drug repositioning signal needs to be validated by in vitro/in vivo studies
Step 2:• Psycholeptics downregulate cytokine signaling• Cytokine signaling are upregulated in IBD
Step 1:• Inverse signals between psycholeptics and IBD
Step 3:• Cytokine signaling is upregulated in IBD• Selected CMAP compounds ameliorate IBD
Abbreviations:• AE Adverse Events• CMAP Connectivity MAP (Broad Institute)• DEGs Differentially Expressed Genes• DPA DisProportionality Analysis• FAERS FDA Adverse Event Reporting System (FDA)• GEO Gene Expression Omnibus (NCBI)• SSA Sequence Symmetry Analysis
Step 1:Detection of repositioning
signals
Step 2:Bioinformatics analysis of data
from open resource
Step 3:Literature mining
and curation
Taken together, drug repositioning is
very valuable approach to deliver drugs, in particular for rare diseases.
Standard model for drug discovery
Forward approach
Reverse approach
Hybrid model for drug discovery
Modified from Lipinski and Hopkins, 2004, Nature
Modified from Hosomi et al., 2018, PLOS ONE
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