1. Biochemistry and Chemical Biology
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Science Forum: Donated chemical probes for open science

  1. Susanne Müller  Is a corresponding author
  2. Suzanne Ackloo
  3. Cheryl H Arrowsmith
  4. Marcus Bauser
  5. Jeremy L Baryza
  6. Julian Blagg
  7. Jark Böttcher
  8. Chas Bountra
  9. Peter J Brown
  10. Mark E Bunnage
  11. Adrian J Carter
  12. David Damerell
  13. Volker Dötsch
  14. David H Drewry
  15. Aled M Edwards
  16. James Edwards
  17. Jon M Elkins
  18. Christian Fischer
  19. Stephen V Frye
  20. Andreas Gollner
  21. Charles E Grimshaw
  22. Adriaan IJzerman
  23. Thomas Hanke
  24. Ingo V Hartung
  25. Steve Hitchcock
  26. Trevor Howe
  27. Terry V Hughes
  28. Stefan Laufer
  29. Volkhart MJ Li
  30. Spiros Liras
  31. Brian D Marsden
  32. Hisanori Matsui
  33. John Mathias
  34. Ronan C O'Hagan
  35. Dafydd R Owen
  36. Vineet Pande
  37. Daniel Rauh
  38. Saul H Rosenberg
  39. Bryan L Roth
  40. Natalie S Schneider
  41. Cora Scholten
  42. Kumar Singh Saikatendu
  43. Anton Simeonov
  44. Masayuki Takizawa
  45. Chris Tse
  46. Paul R Thompson
  47. Daniel K Treiber
  48. Amélia YI Viana
  49. Carrow I Wells
  50. Timothy M Willson
  51. William J Zuercher
  52. Stefan Knapp
  53. Anke Mueller-Fahrnow  Is a corresponding author
  1. Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Germany
  2. University of Toronto, Canada
  3. Bayer AG, Germany
  4. Vertex Pharmaceuticals, United States
  5. The Institute of Cancer Research, United Kingdom
  6. Boehringer Ingelheim, Austria
  7. University of Oxford, United Kingdom
  8. Boehringer Ingelheim, Germany
  9. Institute of Biophysical Chemistry, Goethe-University, Germany
  10. Goethe University, Germany
  11. University of North Carolina at Chapel Hill, United States
  12. Janssen Pharmaceutical Research and Development LLC, United States
  13. Merck & Co., Inc., United States
  14. Ched Grimshaw Consulting, LLC, United States
  15. Leiden University, Netherlands
  16. Takeda California Inc., United States
  17. J&J Innovation Centre, United Kingdom
  18. Eberhard Karls Universität Tübingen, Germany
  19. Pfizer, United States
  20. Takeda Pharmaceutical Company Ltd, Japan
  21. Janssen-Pharmaceutical Companies of Johnson & Johnson, Belgium
  22. Technische Universität Dortmund, Germany
  23. AbbVie, United States
  24. University of North Carolina Chapel Hill School of Medicine, United States
  25. National Institutes of Health, United States
  26. Takeda Pharmaceutical Company Ltd., Japan
  27. University of Massachusetts Medical School, United States
  28. Eurofins DiscoverX, United States
Feature Article
Cite this article as: eLife 2018;7:e34311 doi: 10.7554/eLife.34311
4 figures and 2 tables

Figures

Chemical probes need to fulfil stringent criteria to qualify as research tools.

Shown here are target and compound related criteria applied by the Structural Genomics Consortium.

https://doi.org/10.7554/eLife.34311.002
Typical workflow for a kinase probe discovery project.

Medicinal chemistry optimization involving multiple iterative steps of compound design, synthesis and screening are necessary until probe criteria are fulfilled.

https://doi.org/10.7554/eLife.34311.003
Overview of targets for which pharmaceutical companies have volunteered to donate chemical probes. 

Planned release for wave one probes is in spring 2018 pending the outcome of independent peer review. The targets of this first wave of probes are given in Table 1. Final numbers may slightly vary as some chemical probes are still in the approval process.

https://doi.org/10.7554/eLife.34311.004
Attrition rate and categories of donated probes.

A. Attrition rate of the approval process of the proposed chemical probes. B. Approved probes were categorized to show their differentiation from available chemical modulators (i) targets for which there are currently no high-quality probes available; (ii) targets for which the donated probe promises a significant (e.g. 10-fold) benefit in potency or selectivity; (iii) cases in which the new donated probe has similar potency/selectivity as currently available probes but an entirely different chemotype; (iv) best in class compound where none of the above points apply and where the benefit lies in the availability of the control compound and/or the data annotation.

https://doi.org/10.7554/eLife.34311.006

Tables

Table 1
Targets of first wave of donated probes (approved or close to approval).
https://doi.org/10.7554/eLife.34311.005
FamilyTargetMode of actionCompanyStructure
D4 Dopamine receptorAgonistAbbVie
ABT-724
GPCRETA Endothelin receptorAntagonistAbbVie
ABT-546
Par1/F2R (F2R) Protease activated receptorAntagonistBayer
BAY-386
CRTH2 (Prostaglandin DP2 receptor)AntagonistMSD
CRTH2i
CB1 Cannabinoid receptorInverse AgonistMSD
MRL-650
EP2Prostaglandin receptorAntagonistPfizer
PF-04418948
α1D AdrenoceptorAntagonistTakeda
(R)-9s
KISS1 Receptor (GPR54)AgonistTakeda
KISS1-305
D-Tyr-D-Pya(4)-Asn-Ser-Phe-azaGly-Leu-Arg(Me)-Phe-NH2
HydrolasesEH (Soluble epoxide hydrolase)InhibitorBoehringer Ingelheim
BI-1935
FAAH (Fatty acid amide hydrolase)InhibitorPfizer
PF-04457845
Ion channelTRPM8 (Cold and menthol receptor 1)AntagonistPfizer
PF-05105679
Kinasec-MET (Tyrosine-protein Kinase Met)InhibitorBayer
BAY-474
TIE (Tyrosine kinase with Ig and EGF homology domains 1), DDR (Discoidin domain receptor family)InhibitorBayer
BAY-826
ERK1/2 (Extracellular signal-regulated kinase)InhibitorMSD
MRK-ERKi
SYK (Spleen tyrosine kinase)InhibitorMSD
MRL-SYKi
FAK/PYK2(focal adhesion kinase/proline-rich tyrosine kinase 2)InhibitorPfizer
PF-04554878












Other
FLAP (5-Lipoxygenase-activating protein)InhibitorBoehringer Ingelheim
BI 665915
FASN (Fatty acid synthase)InhibitorBoehringer Ingelheim
BI 99179
MIF (Macrophage migration inhibitory factor)ActivatorTakeda
BTZO-1
FarnesyltransferaseInhibitorAbbVie
ABT-100
P300/CBP(E1A binding protein/CREB binding protein)InhibitorAbbVie
A-485
NHE1, SLC9A1AntagonistBoehringer Ingelheim
BI-9267
MTH1 (MutT homolog 1)InhibitorBayer
BAY-707
ProteaseMMP12 (Matrix metallopeptidase 12)InhibitorBayer
BAY-7598
Gamma secretaseInhibitorMSD
MRK-560
Gamma secretaseModulatorMSD
GSM1
METAP2 (Methionine aminopeptidase-2)InhibitorTakeda
TP-004
Table 2
Overview of data generated for all donated probes.

These data will be made available through a publicly available database.

https://doi.org/10.7554/eLife.34311.007
AssaysScopeTiming
Target-specific assays (biochemical/
biophysical/ cell-based)
All chemical probes & controlsBefore release
(decision criteria)
Target-specific selectivity panels
500+ kinasesAll chemical probes & controlsAfter release
(annotation)
Broad specificity panel, 100+ ion
channels, GPCRs, proteases
30+ epigenetics targets
Phenotypic assays (cell lines &
primary human material)
3D structure of
protein-ligand complex
SubsetOptional
Physchem parameters,
e.g. solubility
Subset
In vivo experimentsSelected probes

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