A really interesting review of the Chemical Probes portal
2020 was the first year of visible activity on the Chemical Probes Portal since 2017, with 115 probes added and over 500 compounds now included on the Portal. To celebrate, we’re highlighting ten of the best probes added to the Portal and evaluated by our Scientific Advisory Board in 2020. These probes are selective, potent, cell-active molecules that are rated four stars for use in cells and target new proteins or have new mechanisms of action. They include probes for previously ‘undruggable’ cancer targets, compounds that target GPCRs, epigenetic modulators and PROTACs.
Full details are here https://www.chemicalprobes.org/news/2020s-top-probes.
The Chemical Probes Portal now includes several PROTACs in the list of recommended chemical probes and even more are under review by the Scientific Advisory Board.
PROTACs are bifunctional molecules that bind to the target protein and an E3 ligase, the simultaneous PROTAC binding of two proteins brings the target protein in close enough proximity for polyubiquitination by the E2 enzyme associated to the E3 ligase, which flags the target protein for degradation through the proteasome.
They have also put together a really useful list of criteria to help define the best choice of Protac probe.
The latest Open Targets Platform 19.09 has been released. The latest release contains
27,024 targets 10,474 diseases 3.33 million pieces of evidence 7.78 million associations between targets and diseases
In addition, a number of Target Enabling Packages (TEP) provided by Structural Genomics Consortium have been included, there are more details here. Several new chemical probes have also been included.
The latest update of the Open Targets Platform, release 19.06 is available.
This update includes
Target safety information
As a follow-up to the safety data in Open Targets Platform release 19.04, now has more targets with known safety effects and safety risk information, including TBXA2R and JAK2.
TEPs and chemical probes
In this release, they've included the latest Target Enabling Packages (TEPs) for GALT, GALK1 and MLLT1. Also added more chemical probes, small-molecule modulators of a protein’s function that can be used in cell-based or animal studies.
A new release always means new evidence available for novel target-disease associations.
As part of the Boehringer Ingelheim's efforts to foster innovation, they are share selected molecules with the scientific community all for free. The opnme portal gives access to a range of novel ligands. The latest addition is BI-9740
BI-9740 is a very potent and highly selective inhibitor of the enzymatic activity of Cathepsin C. It blocks human CatC in vitro with an IC50 of 1.8 nM and shows > 1500x selectivity versus the related proteases Cathepsin B, F, H, K, L and S. BI-9740 displays no activity against 34 unrelated proteases from different classes up to a concentration of 10 µM.
Chemical probes are absolutely essential for target validation and it is great to see so many high quality tools being made available.
To foster innovation, we openly share selected molecules with the scientific community to unlock their full potential - all for free, no hidden costs.
The latest addition is a potent Chymase inhibitor, Chymase is a chymotrypsin-like serine protease that is stored in a latent form in the secretory granules of mast cells. Upon stimulation, it is released in its active form into the local tissue, contributing to the activation of TGF-ß, matrix metalloproteases and cytokines.
BI-1942 is a highly potent inhibitor of human chymase (IC50 = 0.4 nM) that can be used to test biological hypotheses involving this target in vitro. With BI-1829 we also offer a structurally close analog that is more than 1000 fold less active (IC50 = 850 nM) and can thus be used as negative control for in vitro studies.
Boehringer Ingelheim has added it's well-characterised non-covalent ATP-competitive inhibitor of glycogen synthase kinase (GSK-3) Bi-5521 to its open molecule platform opnMe.com.
opnMe.com, the new open innovation portal of Boehringer Ingelheim, aims to accelerate research initiatives and enable new disease biology in areas of high unmet medical need by sharing well-characterized, best-in-class, pre-clinical tool compounds.
BI-5521 is a potent and selective ATP-competitive small molecule inhibitor of glycogen synthase kinase 3 (GSK-3), GSK-3β (IC50) 1.1 nM, with demonstrated in vivo activity. Rat pharmacokinetics are available, together with an inactive related compound.
Another useful tool for Target Validation.
We recently heard that Pfizer is leaving the neuroscience therapeutic area, with a resulting loss of around 300 jobs. This is of course bad news for the scientists involved but I hope the work that was undertaken within Pfizer does not disappear. Chemical probes are critical tools in target identification and validation and arguably even more so in neuroscience. I hope that Pfizer consider releasing some of the well characterised molecules as freely accessible chemical probes, especially if they could also offer a similar but inactive molecule as a negative control. Many of the older tool compounds reported in the literature have been shown to have inadequate selectivity which compromises understanding the biology.
There are many important therapeutic targets within neuroscience but our biological understanding is currently inadequate to justify the investment in drug discovery, a selection of well characterised probes may provide the tools to support the necessary basic biological research.
One of the key challenges to exploring interesting targets is having access to high quality molecular probes. A number of organisations have go together to support Chemical Probes Portal which provides information and independent reviews of chemical probes.
The Chemical Probes Portal is designed to change the way scientists find and use small-molecule reagents called chemical probes in biomedical research and drug discovery. The Portal is backed by reviews and commentary from recognised chemical probe experts. Our knowledge-dissemination model, focused on providing accessible expert advice, promises to increase research reproducibility, maximise investment outcomes and accelerate the discovery science that informs the next generation of therapeutic
Recently Boehringer Ingelheim have decided to provide access to a number of chemical probes.
To foster innovation, Boehringer Ingelheim (BI) is openly sharing selected molecules with the scientific community to unlock their full potential. There are two types of Boehringer Ingelheim molecules that you can access on this portal: some for ordering, some for collaboration.
These molecules cover a range of interesting molecular targets.
|Aurora B inhibitor||BI 831266|
|Autotaxin (ATX) inhibitor||BI-2545|
|FAS inhibitor||BI 99179|
|FLAP antagonist||BI 665915|
|Glucocorticoid Receptor (GR) Agonist||BI 653048|
|Hep. C virus (HCV) NS5B polymerase inhibitor||BI 207127 (Deleobuvir)|
|Hepatitis C virus (HCV) NS3 protease inhibitor||BI-1230|
|Hepatitis C virus (HCV) NS3 protease inhibitor||BI-1388|
|LFA-1 (lymphocyte function-associated antigen-1) antagonist||BI-1950|
|SYK inhibitor||BI 1002494|
Looking at the selective Aurora B kinase inhibitor BI 831266, it is clear that BI is making available high quality molecules, they provide the structure, in vitro activity, together with both in vitro and in vivo DMPK data in multiple species. They also suggest a related compound as a negative control in which the N-Me serves to block the critical hinge binding.
There is also a co-crystal structure and some counter-screening data, together with key references from the literature. Any data generated can be published without approval from BI.
This looks to be a very exciting initiative and it will be interesting to see if other companies follow suit.
They have also created a search engine BI Miner to search multiple data sources simultaneously (PubMed Central, Medline, Patents, Drug labels, Expression Data, NIH Grants, Clinical Trials), this open access.