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