Discovery of drug mode of action and drug repositioning from transcriptional responses

1. Discovery of drug mode of action and drugrepositioning from transcriptional responses Francesco Iorioa,b, Roberta Bosottic, EmanuelaScacheric, VincenzoBelcastroa, PratibhaMithbaokara, Rosa Ferrieroa, Loredana Murinob, Roberto Tagliaferrib, Nicola Brunetti-Pierria,d, Antonella Isacchic,1, and Diego di Bernardoa,e,1 aTeleThon Institute of Genetics and Medicine, Naples, Italy; cDepartment of Biotechnology, Nerviano Medical Sciences, Milan, Italy; eDepartment of Systems and Computer Science, “Federico II” University of Naples, Naples, Italy; dDepartment of Pediatrics, “Federico II” University of Naples, Naples, Italy; and bDepartment of Mathematics and Computer Science, University of Salerno, Salerno, Italy Presenter: Chifeng Ma

2. Structure • Background • Method & Result • Conclusion

3. BackgroundGoal & Key point Drug Mode of Action New drug therapeutic effects /known Drug reposition Drug Signature Extraction Drug Distance Assessment Drug Mode of Action Construction

4. BackgroundData:Connectivity Map

5. BackgroundcMap Data • 1,267 compounds • several dosages • 5 cell lines: HL60, PC3, SKMEL5, and MCF7/ssMCF7 Data size: 22277*6836 Drug treated sample Gene Log fold change: Log2(drug treated/normal)

6. Method & ResultOverview

7. Method & ResultDrug Signature Extraction Notation Initialization • D: the set of all the possible permutations of microarray probe-set identifiers (MPI); • X: a set of ranked lists of probe-set identifiers computed by sorting, in decreasing order, the genome-wide differential expression profiles obtained by treating cell lines with the same drug; • δ: D2 → N: the Spearman’s Footrule distance associating to each pair of ranked lists in X, a natural number quantifying the similarity between them; • B: D2 → D: the Borda Merging Function associating to each pair of ranked lists in X a new ranked list obtained by merging them with the Borda Merging Method;

8. Method & ResultDrug Signature Extraction Spearman’s Footrule Spearman’s Footrule between two samples x and y Number of genes in the sample here m=22283 The rank list place of the ith gene

9. Method & ResultDrug Signature Extraction Borda Merging Function A new ranked list of probes z is obtained by sorting them according to their values in P in increasing order

10. Method & ResultDrug Signature Extraction Prototype Ranked List Generation Once a PRL had been obtained, a signature {p,q} was extracted as the top 250 and bottom 250 as the signature.

11. Method & ResultDrug Distance Assessment Core distance algorithm: Gene Set Enrichment Analysis(GSEA)

12. Method & ResultDrug Mode of Action Construction Distance threshold

13. Method & ResultDrug Mode of Action Construction Community Identification Affinity propagation algorithm • A community is defined as a group of nodes densely interconnected with each other and with fewer connections to nodes outside the group 106 community 1309 nodes 41047 edges (856086 edges total)

14. Method & ResultDrug Mode of Action Construction

15. Method & ResultDrug Mode of Action Construction Community-Mode of Action relationship assessment • Anatomical Therapeutic Chemical (ATC) code --- 49/92 assessable communities significantly enrichment • GO enrichment analysis • MoA-Community assessment

16. Method & ResultDrug Distance Assessment Drug to Community distance Distance between Drug d and drug x Number of drugs in C which has a significant edges with drug d

17. Method & ResultDrug Net (DN) HSP90 inhibitors test • n.28 is closest, composed by the HSP90 in cMap data • n.40 n.63 Na+∕K+-ATPaproteasome inhibitors • n.104 NF-kB inhibitors

18. Method & ResultDrug Net (DN) Test of cycin-dependent kinases(CDKs) inhibitors and Topoisomerase inhibitors Biology experiment was conduct to confirm that TDK inhibitors and Topo inhibitors share the universal inhibitor p21

19. Method & ResultDrug Net (DN) • Search DN for drugs similar to 2-deoxy-D-glucose(2DOG) ---n.1---induce autophagy • Closest Drug--- Fasudil--- never been previously linked to autophagy • Biology experiment to confirm that

20. Conclusion • Developed a general procedure to predict the molecular effects and MoA of new compounds, and to find previously unrecognized applications of well-known drugs • Analyzed the resulting network to identify communities of drugs with similar MoA and to determine the biological pathways perturbed by these compounds. • In addition, experimentally verified a prediction • A website tool was implemented at http://mantra.tigem.it

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23. The End Thank you! Question?