Science Forum: Donated chemical probes for open science
Figures
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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://iiif.elifesciences.org/lax/34311%2Felife-34311-fig2-v2.tif/full/617,/0/default.jpg)
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.
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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.
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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.
Tables
Targets of first wave of donated probes (approved or close to approval).
https://doi.org/10.7554/eLife.34311.005Family | Target | Mode of action | Company | Structure |
---|---|---|---|---|
D4 Dopamine receptor | Agonist | AbbVie ABT-724 | ![]() | |
GPCR | ETA Endothelin receptor | Antagonist | AbbVie ABT-546 | ![]() |
Par1/F2R (F2R) Protease activated receptor | Antagonist | Bayer BAY-386 | ![]() | |
CRTH2 (Prostaglandin DP2 receptor) | Antagonist | MSD CRTH2i | ![]() | |
CB1 Cannabinoid receptor | Inverse Agonist | MSD MRL-650 | ![]() | |
EP2Prostaglandin receptor | Antagonist | Pfizer PF-04418948 | ![]() | |
α1D Adrenoceptor | Antagonist | Takeda (R)-9s | ![]() | |
KISS1 Receptor (GPR54) | Agonist | Takeda KISS1-305 | D-Tyr-D-Pya(4)-Asn-Ser-Phe-azaGly-Leu-Arg(Me)-Phe-NH2 | |
Hydrolase | sEH (Soluble epoxide hydrolase) | Inhibitor | Boehringer Ingelheim BI-1935 | ![]() |
FAAH (Fatty acid amide hydrolase) | Inhibitor | Pfizer PF-04457845 | ![]() | |
Ion channel | TRPM8 (Cold and menthol receptor 1) | Antagonist | Pfizer PF-05105679 | ![]() |
Kinase | c-MET (Tyrosine-protein Kinase Met) | Inhibitor | Bayer BAY-474 | ![]() |
TIE (Tyrosine kinase with Ig and EGF homology domains 1), DDR (Discoidin domain receptor family) | Inhibitor | Bayer BAY-826 | ![]() | |
ERK1/2 (Extracellular signal-regulated kinase) | Inhibitor | MSD MRK-ERKi | ![]() | |
SYK (Spleen tyrosine kinase) | Inhibitor | MSD MRL-SYKi | ![]() | |
FAK/PYK2(focal adhesion kinase/proline-rich tyrosine kinase 2) | Inhibitor | Pfizer PF-04554878 | ![]() | |
Other | FLAP (5-Lipoxygenase-activating protein) | Inhibitor | Boehringer Ingelheim BI 665915 | ![]() |
FASN (Fatty acid synthase) | Inhibitor | Boehringer Ingelheim BI 99179 | ![]() | |
MIF (Macrophage migration inhibitory factor) | Activator | Takeda BTZO-1 | ![]() | |
Farnesyltransferase | Inhibitor | AbbVie ABT-100 | ![]() | |
P300/CBP(E1A binding protein/CREB binding protein) | Inhibitor | AbbVie A-485 | ![]() | |
NHE1, SLC9A1 | Antagonist | Boehringer Ingelheim BI-9267 | ![]() | |
MTH1 (MutT homolog 1) | Inhibitor | Bayer BAY-707 | ![]() | |
Protease | MMP12 (Matrix metallopeptidase 12) | Inhibitor | Bayer BAY-7598 | ![]() |
Gamma secretase | Inhibitor | MSD MRK-560 | ![]() | |
Gamma secretase | Modulator | MSD GSM1 | ![]() | |
METAP2 (Methionine aminopeptidase-2) | Inhibitor | Takeda TP-004 | ![]() |
Overview of data generated for all donated probes.
These data will be made available through a publicly available database.
Assays | Scope | Timing |
---|---|---|
Target-specific assays (biochemical/ biophysical/ cell-based) | All chemical probes & controls | Before release (decision criteria) |
Target-specific selectivity panels | ||
500+ kinases | All chemical probes & controls | After 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 | Subset | Optional |
Physchem parameters, e.g. solubility | Subset | |
In vivo experiments | Selected probes |