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Probe Miner AACR Annual Meeting, Chicago, 2018

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Invited talk presented at the Educational Session on "the use and abuse of chemical probes" chaired by Prof. Paul Workman about the Probe Miner resource and its use to help scientists assess and select chemical probes using publicly available data.

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Probe Miner AACR Annual Meeting, Chicago, 2018

  1. 1. in partnership with Probe Miner Harnessing large-scale public data for the objective assessment of chemical probes Albert A. Antolin, Joe E. Tym, Angeliki Komianou, Ian Collins, Paul Workman & Bissan Al-Lazikani Department of Data Science and Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, UK. 2018 AACR National Meeting, Chicago, USA.
  2. 2. Disclosure Information AACR National Meeting Albert A. Antolin I have no personal financial relationships to disclose. Employee of ICR which has multiple commercial interactions and I will not discuss off-label use and/or investigational use in my presentation. 2
  3. 3. Previous LiteratureOnline search enginesCompound vendor catalogs Limitations of current approaches to chemical probe selection 3 Liu, et al. Clin Cancer Res, 2012 Blagg & Workman, Cancer Cell, 2017
  4. 4. The Chemical Probes Portal and potential for synergies •  Expert-curated resource that recommends probes for specific targets 4 Arrowsmith, et. al., Nat Chem Biol, 2015 Synergistic Genuine PARP inhibitor
  5. 5. Can we exploit large-scale public data for the objective assessment and prioritization of bioactive compounds as potential chemical probes? 5
  6. 6. Methods: Sources of Data •  canSAR (https://cansar.icr.ac.uk/) •  Integrated multidisciplinary curated data 6 Tym, et. al., Nucleic Acids Res., 2016 >150,000 visitors in 2016 > 2.1 M chemical compounds 14.6 M bioactivity data points 2.8 M mutations from patients > 228,000 clinical trials
  7. 7. Chemical probes for the human proteome •  Systematically and objectively analyzing compounds available in public databases as chemical probes 7 Antolin, et. al., Cell Chem Biol., 2018 Human proteome ∼20,171 proteins NAR, 2016 https://cansar.icr.ac.uk/
  8. 8. The Druggable proteome 8 Antolin, et. al., Cell Chem Biol., 2018 Human proteome ∼20,171 proteins NAR, 2016 22 – 40% Druggable proteome Nature Rev. Drug Discov. 2013 Sci. Trans Med., 2016
  9. 9. Probing the liganded proteome 9 Antolin, et. al., Cell Chem Biol., 2018 Human proteome ∼20,171 proteins NAR, 2016 22 – 40% Druggable 11% Liganded 2,220 proteins How well can we probe the biology of this liganded proteome?
  10. 10. Assessing the quality of chemical probes in public databases Minimum-quality criteria 10 Antolin, et. al., Cell Chem Biol., 2018 Human proteome ∼20,171 proteins NAR, 2016 22 – 40% 11% Target Potency ≤ 100 nM Target Selectivity 10-fold >1 protein Cell Potency < 10 µM Workman & Collins, Chem. Biol., 2010
  11. 11. How much of the liganded proteome can we probe? 11 Antolin, et. al., Cell Chem Biol., 2018 Human proteome ∼20,171 proteins NAR, 2016 22 – 40% 11% Target Potency 74% Target Selectivity 40% Cell Potency 55%
  12. 12. Minimally acceptable probes Target Potency, Cell Potency & Target Selectivity 9% We can probe for less than 2% of the human proteome We don’t have the appropiate tools for target validation 12 Antolin, et. al., Cell Chem Biol., 2018 Human proteome ∼20,171 proteins NAR, 2016 22 – 40% 11%
  13. 13. Minimally acceptable probes Target Potency, Cell Potency & Target Selectivity 9% We can probe for less than 2% of the human proteome We don’t have the appropriate tools for target validation 13 Antolin, et. al., Cell Chem Biol., 2018 Human proteome ∼20,171 proteins NAR, 2016 22 – 40% 11% 1.4% We need more and better chemical probes to cover the proteome
  14. 14. Objective and quantitative assessment of chemical probes From fitness factors to scores 14 Workman & Collins, Chem. Biol., 2010
  15. 15. Objective and quantitative assessment of chemical probes From fitness factors to scores 15 Antolin, et. al., Cell Chem Biol., 2018 •  Compound-protein affinity values •  Compound-cell line affinity values •  Compound chemical structures 6 Chemical Probe Scores
  16. 16. Probe Miner website resource User-friendly resource for the objective assessment of chemical probes 16 Antolin, et. al., Cell Chem Biol., 2018 http://probeminer.icr.ac.uk
  17. 17. Overview page Summaries of the data and statistical analysis using our algorithm 17 Antolin, et. al., Cell Chem Biol., 2018
  18. 18. Overview page Easy-to-navigate distribution of the 20 highest-ranking probes 18 Antolin, et. al., Cell Chem Biol., 2018Antolin, et. al., Cell Chem Biol., 2018
  19. 19. Overview Page Compound viewer interactively linked to the distribution 19 Antolin, et. al., Cell Chem Biol., 2018Antolin, et. al., Cell Chem Biol., 2018
  20. 20. Overview Page Compound viewer interactively linked to the distribution 20 Antolin, et. al., Cell Chem Biol., 2018Antolin, et. al., Cell Chem Biol., 2018
  21. 21. Individual chemical probe page Extended details on raw data, protein affinity profile and cross-references 21 Antolin, et. al., Cell Chem Biol., 2018 The image cannot be displayed. Your computer may not have enough memory to open the image, or the image may have been corrupted. Restart your computer, and then open the file again. If the red x still appears, you may have to delete the image and then insert it again.
  22. 22. The Chemical Probes Portal & Probe Miner SYNERGIES 22
  23. 23. PARP1: Large-scale assessment highlights recent data 23 Antolin, et. al., Cell Chem Biol., 2018
  24. 24. Probe Miner and The Chemical Probes Portal: Overall synergy 24 Antolin, et. al., Cell Chem Biol., 2018 Larger number of publications and data assessed Information from journals not covered by public medicinal chemistry databases and in depth analysis of selectivity and in vivo data.
  25. 25. ABCC8: wider coverage of Probe Miner Probe Miner 2,220 targets; The Chemical Probes Portal > 140 targets 25
  26. 26. PDPK1: the value of expert curation in the Portal and the challenge of automatically assessing selectivity 26 Challenging comparison when information varies significantly #1 #2
  27. 27. SMYD2: The value of regular updates of information 27 Data Update
  28. 28. Future Plans •  We will maintain Probe Miner and update it regularly to ensure topicality •  We are already liaising with The Chemical Probes Portal to identify new probes for expert assessment •  We are already starting to extract and include selected chemical biology data from a wider range of journals that are currently missing from medicinal chemistry databases 28
  29. 29. Conclusions •  Probe Miner: objective assessment of potential chemical probes from large-scale literature data •  We do not have enough high-quality chemical probes: selectivity is the biggest hurdle •  We urgently need to test selectivity more thoroughly and improve how this data is captured in public databases •  Synergy from the complimentary use of the experience and knowledge of experts with large-scale computational data analysis. 29 <2%
  30. 30. in partnership with Thank you! Bissan Al-Lazikani Paul Workman DEPARTMENT OF DATA SCIENCE Joe Tym Angeliki Komianou Elizabeth Coker Costas Mitsopoulos Carmen Rodriguez-Gonzalvez Veronica Garcia-Perez Sheng Yu Catherine Fletcher Sebastian Poetsrl James Campbell Patrizio di Micco STMP Team Paul Clarke Chi Zhang Alexia Hervieu Ian Collins

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