Prepared as visitor seminar for PubChem, April 2013

1. Digging out Structures for Repurposing:
Non-competitive Intelligence
PubChem Seminar April 2013
Christopher Southan, TW2Informatics, Göteborg, Sweden
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2. Dr Christopher Southan, Ph.D., M.Sc.,B.Sc.
TW2Informatics: http://www.cdsouthan.info/Consult/CDS_cons.htm
Mobile: +46(0)702-530710
Skype: cdsouthan
Email: cdsouthan@hotmail.com
Twitter: http://twitter.com/#!/cdsouthan
Blog: http://cdsouthan.blogspot.com/
LinkedIN: http://www.linkedin.com/in/cdsouthan
Publications: http://www.citeulike.org/user/cdsouthan/order/year,,/publications
Presentations: http://www.slideshare.net/cdsouthan
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3. Outline
• Trawling for repurposing-relevant data
• Code names statistics and name > structure triage
• The NCATS/MRC challenge
• Story of JNJ-39393406
• Scaling-up Code name hunting and x-mapping
• Code name in clinical trials, MeSH, PubChem
• Story of PF-04457845
• Trials, MeSH and PubChem code name intersects
• Conclusions
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4. Intelligence: trawling compound information
Competitive Non-competitive
• Directed towards commercially • Directed towards repositioning any
positioning and/or repurposing compound
own portfolio • Collaborative approaches to IP
• Major big pharma activity holders (but new IP possible)
• Mixed commercial/public sources • Can utilise public resources alone
• Internal specialists • Different domain expert entry
• Typically a closed activity (i.e. little points
open “best practice”) • Predominantly an open activity
• Typically therapeutic area aligned (e.g. OSDD)
• Can be hypothesis-neutral
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5. Structures:
connecting to repurposing-relevant data
• Code names and synonyms
• Resolving these to structures
• Database entries
• BioAssay results
• Target/pathway links
• In vitro & in vivo research papers
• Clinical trial results and papers
• Patents for analogues and SAR
• Comparative in vivo data
• Mendelian and GWAS disease links
• Expression data for cpds
• In silico modeling (including rare or NTDs)
• Vendor similarity matches
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6. Code names: 2-15 year information hole
Pharmaprojects
2009-10 figures
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7. Drugs,code names, INN/USANs and structures:
few congruent hard numbers
• Pharmaprojects (2013) drug profiles ~ 50,000
• Thomson Reuters Cortelis (2012) drug monographs = 41,889
• Pharmaprojects (via ProQuest, 2012) records ~ 35,000
• Thomson Reuters Partnering (2011 structures, PMID: 22024215) = 17,901
• Pharmaprojects (2003 structures) = 14,000
• ChEMBL USANs (2013) = 10,568
• PubChem (2013) “USAN [synonym] OR INN [synonym]” = 9,890
• Pharmaprojects (2010 in development, no structure count) = 9,737
• GVKBIO Clinical Candidate structures (2008, PMID:20298516) = 8,864
• Pharmaprojects (2010 review, no structures) Phase 1+2+3 = 3,828
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8. Code names: major repurposing potential – but..
• ~ 95% of the 30K are/will become “parked” or “abandoned”
• Can be repurposed in silico at least
• Obvious hierarchy : leads> development > clinical trials > INN > approved
• Problems
– New code names < 50% - 70% blinded (i.e. no structures)
– Some older code names never un-blinded
– Code naming practices independent and completely ad hoc
– Publications, conference reports, clinical trials entries, press releases
and portfolio listings linked to “blinded” code names (no structures)
– Even for public declarations (e.g. papers) data linked into “the system”
(e.g. synonym mapping) is patchy
– Code originators do not provenance public database entries
– Data supporting non-progression decisions rarely disclosed
– http://chembl.blogspot.se/p/research-code-stems.html 100’s of codes
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9. Code name-to-structure mapping triage
Dig out the code names Name/image > struc
PubChem Substance • chemicalize.org, OPSIN,
Chemical Identifier Resolver,
PubChem Compound sketchers, OSRA
PubMed/MeSH • Cross-checks:
– SMILES/SDF/InChI strings
PubChem and ChemSpider
Google Scholar – InChIKey in Google
– SureChemOpen patent search
Google Images – Clinicaltrials.gov
– Synonym trawling
Google open (filtered)
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10. The NCATS/MRC industry sponsored
repurposing exercise: the joy of code lists
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11. NCATS/MRC repurposing candidates
http://cdsouthan.blogspot.se/2012/09/mrc-22-vs-ncats-58-repurposing-lists.html
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12. NCATS/MRC: summary statistics
PMID 23159359
• 70 code names – no structures
• 18 INNs & 4 codes-only in PubChem
• 24 strucs “dug out” but PubChem-ve
• 24 codes remain blinded
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13. Sleuthing down a JNJ-39393406 structure:
from darkness to twilight
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14. JNJ-39393406:NCATS documentation PubChem -ve
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15. JNJ-39393406: ClinicalTrials.gov
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16. JNJ-39393406 in PubMed
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17. JNJ-39393406: open Google
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18. JNJ-39393406: Google Scholar (was) structure -ve
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19. JNJ-39393406 in Google images: finally a mapping
But where did these two vendors get their mapping from ?
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20. (Probable) JNJ-39393406 in PubChem:
CID 1675566 patent-only sources and near-neighbours
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21. (Probable) JNJ-39393406:
SureChemOpen patent match
with corroborative data
PubChem SID 152835708
Cf NCATS data
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22. More JNJ-39393406 mystery:
InChIKey in Google > ChemSpider > 3rd vendor
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23. Not all JNJ-s are blinded: JNJ-40418677
IUPAC in abstract but code still PubChem –ve
IUPAC name converted at chemicalize.org for PubChem mapping
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24. Scaling-up code name retrieval:
wild card searches
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25. Phases & codes in Clinicaltrials.gov:
thin on results
• Interventional studies = 115356 , 7895 with results (7%)
• Results | Interventional Studies | Phase 1, 2, 3 | Industry = 4477
• Interventional Studies | GSK* | Phase 1, 2, 3 | Industry = 1004
• Results | Interventional Studies | GSK* | Phase 1, 2, 3 | Industry = 122 (12%)
• Interventional Studies | GSK* OR AZD* OR JNJ* OR PF0* | Phase 1, 2, 3 |
Industry = 1640
• Results | Interventional Studies | GSK* OR AZD* OR JNJ* OR PF0* | Phase
1, 2, 3 | Industry = 185 (11%)
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26. altrials.net: public pressure > more results > more
repurposing opportunities
http://www.youtube.com/watch?v=lQ6YTU5kGXw&fe
ature=youtu.be&t=28m39s
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27. Stemming code names in MeSh
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28. Code names in PubChem Compound (CIDs)
CID:SID ratio 275:1039 [28]

29. Codes in PubChem: selected matches
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30. “GSK-” in ChEMBL : 61
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31. Tracking PF-04457845 through the system
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32. PubMed intersects: finding PF-04457845
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33. PF-04457845:
PubMed
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34. PF-04457845: Clinicaltrials.org
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35. PF-04457845:
PubChem CID
24771824
Substance (SID)
capture of activity,
vendor and patent
sources
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36. Wikipedia: links to other development compounds
But who put them in ?
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37. PF-04457845: (almost) a total system success
• Declared efficacy failure > possible repurposing candidate
• Selection of analogues and a probe [18F]PF-9811 (CID 70679467)
• The “system” did well because of good publishing practice (e.g. full text)
• Code, structure, target, papers, trials and patents all connected
• 5mg for $275
But-
• Serendipitous finding (no “efficacy failure” or “study stopped” tags)
• Lack of clinicaltrials.org <> PubMed
• BindingDB using deprecated ChEBI ID
• PMID:21505060 not yet in ChEMBL
• No direct target or patent nos. in CID record because no DrugBank,
SCRIPDB or IBM capture
• [18F]PF-9811 PubChem, [(18)F]PF-9811 PubMed, PF-9811-18F Books
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38. Looking at code name intersects in different
parts of the system
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39. Clinicaltrials.org JNJ* Word cloud
JNJ-28431754 = Canagliflozin = CID 24812758
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40. Company Pipelines: GSK codes for 2012
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41. GSK codes: PubChem vs. 2012 Pipeline
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42. Clinical Trials, PubChem, MeSH: GSK
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43. Clinical Trials, PubChem, MeSH: JNJ
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44. Clinical, PubChem, MeSH, & 2012 Pipeline:GSK
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45. Conclusions
• Stalled development candidates, designated by company codes,
constitute a large potential repurposing information estate
• Historical in vitro , pharmacological & clinical data linked to ~ 30K codes
• But only 40-50% have structures assignable from open sources
• An even smaller proportion have code names in PubChem
• Public name>struc>data capture is ad hoc and needs improving
• Repurposing-relevant relationships are not easy to dig out
• Some “non competitive intelligence” approaches are shown here
• The big push for transparency and open access should improve
disclosure, data capture, linkage and repurposing opportunities
Happy hunting !
TED Talk: Francis Collins: We need better drugs -- now
http://www.ted.com/talks/francis_collins_we_need_better_drugs_now.html
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