Science Talk

A decade on from their call-to-action paper, Ben Kolbington speaks with the Chemical Probes Portal team about the progress they've made and what they still hope to achieve in their mission to improve the quality and robustness of biomedical research.

10 years ago, leading chemical biologists and drug discovery scientists from around the world united to address an issue that was plaguing both fundamental and applied biomedical research – that scientists were regularly using low-quality chemical compounds that were incorrectly claimed to be high-quality as chemical probes in their experimental work. And also, commonly misusing even the higher quality ones.

On 21 July 2015, Nature Chemical Biology published a call-to-action paper from the expert team that drew attention to the issue, and which also announced their plans to launch what would become the Chemical Probes Portal – a public online resource which aimed to improve the quality and robustness of biomedical experiments.

The authors of the clarion-call article, who included the ICR’s drug discovery scientist and then Chief Executive Professor Paul Workman, were expert researchers from more than 40 different organisations representing academia as well as the biotech and pharmaceutical industries. Together they wanted to create a ‘Trip Advisor’ style platform for crowdsourcing expert reviews of the vital small-molecule tools known as chemical probes.

What are chemical probes and why do they need to be correctly used?

Chemical probes are crucial in research – these small molecules are often used to determine the function of a given protein in cells and organisms by blocking its activity. Another important role is in the validation of proteins as therapeutic targets and acting as pathfinders for subsequent drug discovery. Chemical probes are powerful and highly versatile tools that act in a complementary way alongside biological techniques to stop or affect the function of a protein.

However, to be effective as high-quality chemical probes in cell culture studies, these small-molecule reagents, usually inhibitors, must not only act on the protein of interest with high potency – but must also be shown to be very strongly selective for that desired protein target, in other words avoiding unwanted effects on other proteins in the cell or organism under study. Additional essential features include evidence of penetration into the cell, engagement with the protein target, and not being toxic to the cell at concentrations required for them to work effectively.

Furthermore, to be useful in experimental organisms, such as mice, high-quality chemical probes also need to achieve adequate pharmacokinetic exposures in blood and tissues, demonstrate target modulation therein, and be well-tolerated at the doses employed.

Only if the above criteria are met can the chemical probe be used with confidence to interrogate the particular protein target of interest in experimental systems.

Thousands of small-molecule reagents, many of which are poorly characterised or have major flaws, are available to researchers to use in their experiments – but, if chosen and used incorrectly, the findings are often not robust and incorrect conclusions are then drawn. In extreme cases, poorly chosen chemical probe can have expensive consequences and even contribute to the failure of drugs in late-stage clinical trials.

Making an impact on the scientific community

In 2015, when the Nature Chemical Biology paper was published, Professor Workman, who has served as Executive Director of the Chemical Probes Portal since 2018, said that the use of low-quality chemical probes was “causing much confusion, damaging the quality of important research studies, misleading scientists, wasting time and money – and ultimately slowing down the search for new cancer drugs.”

Commenting now, Professor Cheryl Arrowsmith, Chief Scientist of the Structural Genomics Consortium (SGC) at the University of Toronto and co-author of the 2015 paper, said:

“We noticed that many biologists, not trained in chemistry or chemical biology, often used chemical reagents without critical assessment of their on-target and off-target activities and properties. We realised that a resource was needed to help guide the non-specialist scientists to choose the best chemical tool for their experiments.”

In the 10 years since its publication, the paper has been cited by other researchers more than 920 times – demonstrating its impact on the scientific community.

And the Chemical Probes Portal itself has not only served as the hoped-for platform for providing free, all-in-one place, expert advice on chemical probes, but has also become an educational hub, providing clear guidance on probe selection, best-practice usage, and misuse avoidance.

It is fulfilling its mission to empower researchers working on biological and biomedical studies that rely on on-target activity and careful controls to achieve robust findings.

Commenting on its success so far, Professor Workman said:

“From the initial grand vision and inevitably small beginnings, I’m proud to see the tremendous growth of the Portal – which now hosts close to 1,200 compounds, covering over 610 protein targets, and features a total of more than 1,600 probe assessments and rating scores provided by our amazing panel of 250 Scientific Expert Reviewers. In addition, our Portal website provides a wealth of information on selecting and using chemical probes in biomedical research.”

Furthermore, the Portal has reacted quickly to new developments in chemical biology and drug discovery by including chemical probes that work in innovative new ways, especially so-called PROTACs and molecular glues that cause degradation rather than simple inhibition of the protein of interest.

Expanding coverage and reaching even more researchers

But despite the progress made, there is a clear recognition from experts in the field and the Chemical Probes Portal team that there is still much work to be done. Thus, Professor Workman said:

“We do still have a long way to go to expand our protein coverage, incorporate more exciting new chemical modalities, and also reach out further to experimental biologists who are commonly not aware either of the challenges we face with chemical probes or the solutions that we offer on the Portal.”

While there may be work still to do, with more than 1,600 chemical probe reviews in the 10 years since the international team raised the alarm, it’s clear that the Chemical Probes Portal has been helping researchers around the world to make vital discoveries to advance basic biological knowledge and human health.