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Southan BIA 10-2474 Pharmacology 2017

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These slides will be presented at the Pharmacology 2017 meeting in London during the following session:

Abstract Number: OB073
Abstract Title: Capturing new BIA 10-2474 molecular data in the IUPHAR/BPS Guide to PHARMACOLOGY
Date: Wednesday, December 13, 2017, 11:30 AM
Oral Session: Oral Communications: Mixed Tracks

Published in: Science
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Southan BIA 10-2474 Pharmacology 2017

  1. 1. Capturing new BIA 10-2474 molecular data in the IUPHAR/BPS Guide to PHARMACOLOGY Christopher Southan, Elena Faccenda, Simon J. Harding, Joanna L. Sharman, Adam J. Pawson, Stephen. P. Alexander* and Jamie A Davies IUPHAR/BPS Guide to Pharmacology, University of Edinburgh, Deanery of Biomedical Sciences, UK, * Molecular Pharmacology, University of Nottingham Medical School, UK. 1
  2. 2. Abstract (will not be shown, online at Slideshare and BPS) Introduction: In January 2016 a Phase I trial of BIA 10-2474 in France caused the death of one patient and the hospitalisation of others. Given the seriousness of this event it becomes crucial to collate and track both old and new molecular pharmacological data appearing in the peer reviewed literature and patents to facilitate mechanistic insights.The IUPHAR/BPSGuide to PHARMACOGY (GtoPdb) serves as an expert-curated nexus of exactly this kind of information [1].We had already curated entries for FAAH inhibitors (target id 1400) and BIA 10-2474 (ligand id 9001). This presentation describes our work on updating related entries up to August 2017. Methods:We explored PubMed and PubMedCentral for papers related to 10-2474, FAAH inhibition and putative off-targets.The majority of publications were opinion and/or recommendation papers so it was necessary to triage these to find new molecular data.We combed through to find quantitative in vitro verified interactions [2].These were curated into new entries in release 2017.5. Any additional data published in the next four months that passes our quality threshold will be updated for release 2017.6 and included in this presentation. Results: 16 PubMed entries retrieving with "BIA 10-2474" included a detailed secondary clinical report from consultants for the French authorities (PMID 27806235). By adding PMC full-text papers not picked up by PubMed indexing we triaged 20 papers.Two contain experimental data and two are off-target modelling studies.The key paper in this set (PMID 28596366) included activity-based protein profiling to detect off-target proteinsWe have consequently expanded FAAH inhibitors to 17, including 10-2474 metabolites from posters presented at BPS Pharmacology 2016. Conclusion: In the 18 months since the 10-2474 event we could find only one paper to curate new quantitative molecular interaction data from.This slow response of the pharmacology community in generating data that could contribute to our molecular toxicological understanding is cause for concern (although compound availability may have been a limiting factor). We are aware of at least one other molecular paper in preparation. We will thus continue to expand our relationship capture as a global resource in this domain.This will include data-supported off targets and active metabolites as part of the push towards a mechanistic understanding of the tragedy. References: [1] Southan et al. (2016). Nucl. Acids Res. 44 (Database Issue): D1054-68. [2] https://cdsouthan.blogspot.se/2016/01/molecular-details-related-to-bia-10-2474.html 2
  3. 3. Outline • GtoPdb introduction • January 2016 - getting it wrong • Getting BIA 10-2474 right • Current PubChem entries • BIAL presentations • PubMed search • What we curated • Our current FAAH inhibitor list • Modelling • Conclusions 3
  4. 4. Introduction to the IUPHAR/BPS Guide to Pharmacology (GtoPdb) • IUPHAR = International Union of Basic and Clinical Pharmacology, BPS = British Pharmacological Society • Formerly know as IUPHAR-DB for receptors and channels since 2003 • Since 2012 funded byWellcomeTrust to cover all targets in the human genome • Curated molecular mechanism of action (mmoa) as quantitative activity mapping to primary targets, including IUPHAR nomenclature • 1690 human proteins with 15428 curated interactions, 9064 ligands • Described in six Nucleic Acids ResearchAnnual Database issues, the latest as PMID 26464438 (2016) and PMID 29149325 (2018) • Distilled into the biennial BritishJournal of Pharmacology “Concise Guide to PHARMACOLOGY” as a nine-paper series (see PMID 29055037) • Presents users with the best compounds for pharmacology research in silico, in vitro, in cellulo, in vivo, and in clinico 4 http://www.guidetopharmacology.org/
  5. 5. Nature News, 21 Jan 2016 5
  6. 6. Working in the dark: blogpost initially picks the wrong structure 6 15th Jan 2016 https://cdsouthan.blogspot.se/2016/01/the-unfortunate-case-of-bia-10-2474.html
  7. 7. GtoPdb entry for BIA 10-2474 7 21 Jan 2016 protocol made public by Le Figaro included IUPAC name Ligand ID 9001 5th Feb 2016
  8. 8. BIAL have presented data • A global overview of toxicological data on BIA 10-2474, Hayes & Weber, 38th American College ofToxicology, Palm Springs, 5-8 November, 2017 • Pharmacological Profile of BIA 10-2474, a Novel FAAH Inhibitor, in the Rat, FASEB abstract, April 2017 • BPS Dec 2016 8
  9. 9. Current PubChem submitters 9
  10. 10. 10 PubMed search • 18 matches as of December 2017 • Eclectic mix • Two data papers • One on modelling • One clinical report • None from BIAL
  11. 11. • We do not generally add GtoPdb records of in vivo or extract data only • We look for in vitro quantitative biochemical target characterisation data provenanced by a PMID • Omission of purified rat enzyme data in this paper seems a lost opportunity 11 What we did not curate: PMID 27650910
  12. 12. 12 But we did curate PMID 28596366
  13. 13. FAAH inhibitors in GtoPdb 13
  14. 14. Does modelling bring anything to the party? 14
  15. 15. Conclusions • GtoPdb BIA 10-2747 molecular characterisation data is from just one paper • Still no consolidation of irreversibility in vitro • We have curated an extended set of other clinical FAAH inhibitors • These facilitate comparative experiments between matched chemotypes and low- activity controls (including from patent data) • Very little published FAAH2 data • The reluctance of the pharmacological community (i.e. not just BIAL) to publish 10- 2747 mechanistic toxicology data in the last two years is concerning • This stands in contrast to the numerous commentary and opinion papers • In silico modelling for off-targets is useful but experimental validation is essential • No linked data in PubChem BioAssay • CAS 1233855-46-3 has neither name nor standard rendering of the pyridine N-oxide • No clinicaltrials.gov entry (115 BIAL entries) despite NEJM trial paper PMID 27806235 • Lets hope 2018 brings new data that GtoPdb can surface to the community 15
  16. 16. Thank you; questions welcome 16 https://cdsouthan.blogspot.se/2016/01/molecular-details-related-to-bia-10-2474.html?q=BIA+10-2474 https://www.ncbi.nlm.nih.gov/pubmed/29149325

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