The Chemical Probes Portal is a free, online resource to help scientists to find and use high-quality chemical probes in biomedical research and drug discovery. It’s one of the leading initiatives from the international, expert chemical probes community, which is seeking to increase the use of better-quality chemical probes in experimental studies across the world and to promote best practice to enhance the robustness of biomedical research.
Chemical probes are very well-characterised small molecules, usually inhibitors, which affect the activity of a specific protein target. They are often used in biological research, for example to investigate the function of the target protein in biological models and to validate potential new drug targets.
But the use of poorly-chosen chemical probes is widespread – especially in biology – leading to misleading experimental results.
A range of criteria are used to assess the quality of chemical probes. A particularly important property is the selectivity of a chemical probe – that is the preferential action of the probe against the intended protein as compared to other proteins in the same family and also additional, unrelated protein families.
With a well-characterised and broadly profiled chemical probe in hand, and following best-practice guidelines, a researcher can have greater confidence that effects seen in cells or animals are indeed a result of the modulation of the intended protein.
Relaunch
Originally established in 2015, the Chemical Probes Portal was relaunched and refreshed in 2021, when the team opened its newly, extensively rebuilt website, released 115 new probe compounds, and added more than 200 new expert reviews.
The Portal team also added 80 new protein targets including, for the first time, those acting as PROTACs, degraders and molecular glues – in addition to the more traditionally-acting inhibitors and agonists, to its selection of small-molecule probes.
The Portal now contains more than 700 compounds, covering 300 protein targets. Recent interesting additions include STM2457, a first-in-class METTL3 RNA methyltransferase inhibitor, the BCL6 degrader BI-3802, and AZD1332 – an NTRK1/NTRK2 kinase inhibitor. You can read more about some of the Portal’s new probes in this blog from Dr Domenico Sanfelice, Chemical Biology Curator at The Institute of Cancer Research, London.
Expert reviews
The Chemical Probes Portal has been developed with the support of bodies including the Structural Genomics Consortium (SGC), Cancer Research UK and more recently a major Biomedical Research Resource grant from Wellcome. Now hosted at the ICR, the Portal is underpinned by the work of around 200 active experts in medicinal chemistry, chemical biology and drug discovery from around the world, who contribute expert reviews and guidance on the use of every uploaded probe.
The expert review process is part of what makes the Portal unique, as Dr Susanne Müller-Knapp, Director of Operations for the Portal and Chief Operating Officer for the Structural Genomics Consortium, Frankfurt, explains. “Three experts review each compound submitted to the Portal and give it a star rating. We recommend that compounds with the highest ratings of three or four stars can be used as chemical probes to investigate their protein target.”
“For a high-quality probe, we want to see a compound that is very selective for the desired protein target, with broad selectivity profiling within the protein family but also outside the family. We also need evidence of target engagement and activity within cells. And we want to see researchers use these probes at the appropriate concentration in cells. In addition, for use in vivo – most commonly meaning mouse models – we also need to see acceptable pharmacokinetic and pharmacodynamic data as well as information about the appropriate dose.”
“For best practice, we further suggest researchers use appropriate controls, including two chemically distinct probes and an inactive control that is a chemical analogue of at least one of them, as well as biological controls including genetic knockdown of the protein target if possible.”
Improving quality and robustness
Chemical probes represent one of the major research interests of Professor Paul Workman, who is Harrap Professor of Pharmacology and Therapeutics at the ICR and Executive Director of the Portal.
Professor Workman said, “With the Chemical Probes Portal, our aim is to give the broader research community an easily accessible resource, underpinned by assessments from world-leading experts in the use of the best chemical probes for the study of particular proteins. Also important is that the new Portal provides an expanded range of information that researchers will find useful in planning their research with chemical probes.
“We certainly hope that our newly enhanced Portal will increase the selection and use of the best chemical tools available and in so doing will contribute to increasing the quality and robustness of biomedical research.
“It takes years of work to get a really good quality, well-characterised probe” Professor Workman continues. “In the past, compounds emerging from chemical screens have been used as chemical probes when they have not undergone sufficient chemical optimisation or detailed mechanistic biological profiling. Many compounds that continue to be used as chemical probes are, quite frankly, promiscuously acting compounds that should never be used – or they may simply have one or a few particular off-target effects that will need to be considered in the given experimental setting. Also to note is that chemical probes evolve over time, with compounds that are useful as initial pathfinders eventually being replaced by more selective chemical probes.”
“We want to give researchers access to up-to-date expert advice, so that they only use the best chemical probes in their research and are made aware of any limitations that apply.”
Big data
One of the major updates from the Portal’s previous iteration is a new capability to sift through massive datasets, recommending interesting compounds to consider as probes for subsequent expert analysis. Data sources include the ICR’s canSAR, the world’s largest public cancer drug discovery resource, and the ICR’s Probe Miner, a leading community resource for the objective evaluation of chemical probes based on large-scale medicinal chemistry, pharmacology and chemical biology data.
Professor Bissan Al-Lazikani, formerly Head of Data Science at the ICR and now Professor of Genomic Medicine at the MD Anderson Cancer Centre, Houston, is Director of Informatics and Technologies on the Portal leadership team. She says, “While expert peer review remains the critical basis for the Portal’s assessment and recommendation of chemical probes, we also want to ensure that both our expert reviewers and the broader research community benefit from access to a distillation of the huge volume of highly relevant data as well as tools that provide an objective analysis to complement the peer review assessment."
The future
Over the next year, the Chemical Probes Portal team aims to add more compounds for more targets and more expert reviews, alongside driving greater awareness of its transformative potential on international research – including through a range of communications targeting the international biology community.
“Selecting good compounds is really important, but also hard, which is where the Portal comes in. You have a ready made set of selective tools with helpful comments from expert reviewers on how best to use them. We need to spread the word – a better choice of compound leads to better science and more robust findings.” says Dr Ben Bellenie, Senior Staff Scientist in the ICR’s Medicinal Chemistry Team 4 and a member of the Portal’s Scientific Expert Review Panel.
“The aim is to increase the number of high-quality compounds being used in biomedical research, by providing up to date information about the quality of chemical probes” explains Professor Workman.
“The Portal is already used by 1,500 visitors per month around the world. But we still need to get the message out more widely, particularly to the biological research community that are using chemical probes. There continue to be multiple examples where use of poor reagents results in erroneous conclusions in publications, and incorrect decisions being made in drug discovery and development.” says Professor Workman. “Which is why we have an active communications and outreach programme directed towards lab researchers, journal editors and grant funders. Also, we’re working closely with the Target 2035 initiative which aims to discover probes for the entire human proteome.
“I’d strongly recommend using the Portal for your own research and when reviewing papers or experimental research – and also encourage your teams and colleagues to do the same,” says Dr Sanfelice. “We need to work together to improve biological research and drug discovery and get better treatments for patients, faster.”
“If there’s a new chemical probe you want to see on the Portal, or a protein target you think we should feature, please let us know. If you’re a Principal Investigator or senior researcher please consider joining our list of expert reviewers. And if you have any questions about chemical probes or the Portal, please get in touch with any member of the team or through the website!”
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