Researchers call for improved use of chemical tools to solve crisis in biomedical research

• Scientists call for improved use of chemical probes to strengthen foundations of fundamental research and drug discovery

• Chemical Probes Portal aims to address systemic issues of quality and robustness in biomedical research

• Target 2035 aims to develop a probe for every human protein to increase and improve the use of chemical probes

Experts in biomedical research are calling for better use of chemical probes to improve our understanding of protein function and the foundations on which much of modern drug discovery and development are based.

In an interview in Nature Communications, published today (Tuesday), Professor Paul Workman, Harrap Professor of Pharmacology and Therapeutics at The Institute of Cancer Research, London, and Professor Cheryl Arrowsmith, Chief Scientist for the Structural Genomics Consortium (SGC) Toronto laboratories and Professor of Medical Biophysics at the University of Toronto, outline the key problems using chemical probes in biomedical research, and highlight new projects to increase the number and quality of chemical tools available to researchers.

Chemical probes are small molecules that are used to test the activity of a protein in a cell, often inhibiting it.

One of the projects discussed is a new, enhanced version of an easy-to-use online resource for chemical probes. The Chemical Probes Portal, relaunched in 2021, relies on expert review carried out by a 200-strong international community of researchers in chemical biology, chemistry and pharmacology, and is supported by big data analysis.

The Portal aims to address a central problem in biomedical research by encouraging the use in laboratory experiments of higher-quality, better-chosen chemical probes – the molecular tools, usually protein inhibitors, which facilitate understandings of biological processes, and which are important to underpin the conclusions of research.

Target 2035 is a research community initiative to accelerate developing a chemical probe for every protein in the human proteome by 2035. Led by the SGC, Target 2035 brings together scientists from diverse areas of drug discovery including biochemists, structural biologists, medicinal chemists, assay scientists and computational chemists.

With a focus on open, collaborative science and new technologies, Target 2035 aims to speed up the development of new, high-quality, chemical probes for the 90% of human proteins that have not yet been studied for potential drug discovery.

Chemical probes are powerful tools used routinely to tease out how individual proteins are involved in health and disease, including in cancer, dementia, and recently Covid-19, and ultimately lead to the discovery of new drugs.

But the quality of these reagents varies widely and the use of sub-optimal tools in research is widespread. Using poor or badly selected compounds as tools can produce misleading results.

Better use of chemical probes could also save the biomedical research sector billions of pounds, by ensuring that new therapies for disease are developed from better, more robust understanding of their biological effects, and therefore are less likely to fail in costly clinical trials.

Developed by scientists at The Institute of Cancer Research (ICR) with the support of bodies including the Structural Genomics Consortium (SGC), Wellcome and Cancer Research UK, the new Chemical Probes Portal aims to encourage the widespread selection and use of the most suitable high-quality chemical probes, particularly within the academic biology community.

One of the major updates from the Portal’s previous iteration is a new process to sift through massive datasets, recommending interesting compounds to consider as probes for subsequent expert analysis.

Researchers from across academia and industry can also submit promising tools to the Portal, which will be reviewed by an expanded panel of nearly 200 experts before information is published for free to researchers across the world.

Other major updates to the Portal include information and expert opinion on hundreds of new chemical tools.

They include inhibitors for proteins previously considered largely undruggable, such as KRAS, agonists for cell surface receptor molecules, GPCRs, including the serotonin receptor HTR2A, as well as new chemical tools such as PROTACs and molecular glues – dual functional molecules that guide proteins to the cellular degradation system to be broken down.

In the last year alone, the number of probes listed on the Portal has increased by 60% to 520. Hundreds of new protein targets have been added, increasing the variety of tools that researchers can use, and broadening the impact in different research areas, including neurology and immunology.

Data sources include the ICR’s canSAR, the world’s largest public cancer drug discovery resource, and Probe Miner, a leading community resource for the evaluation of chemical probes based on large-scale medicinal chemistry data.

The artificial intelligence-enabled canSAR contains data on 500,000 protein structures and three million cavities on the surface of nearly 110,000 macromolecules, which are all annotated and curated so that machine learning algorithms can easily parse through the data, as well as clinical and other data.

Probe Miner has evaluated more than 1.8 million small molecules for their potential to act as chemical probes against 2,200 human protein targets.

Dr Albert Antolin, ICR Fellow and Junior Team Leader at The Institute of Cancer Research, London, and one of the lead researchers in the Chemical Probes Portal, said:

“The Chemical Probes Portal has a host of new updates including detailed information on hundreds of new molecules, a more efficient use of big data and, most importantly, renewed support from hundreds of leading international experts in the best use of chemical probes in research.

“The portal provides all the key information to support the selection of chemical probes in an easy-to-use way. It helps guide the use of chemical probes in thousands of experiments, laying more solid foundations for fundamental research and drug discovery in a wide range of diseases including cancer.”

Professor Paul Workman, Harrap Professor of Pharmacology and Therapeutics at The Institute of Cancer Research, London, and Executive Director of the Chemical Probes Portal, said:

“The incorrect selection and use of chemical probes is widespread in biomedical research and, unfortunately, leads to misleading or wrong conclusions being drawn from the results of experiments. In extreme cases, it can derail drug discovery and clinical trials and lead to the unnecessary waste of hundreds of millions of pounds of research funding.

“With the Chemical Probes Portal, and its close interaction with the Target 2035 initiative, our aim is to give the research community an accessible resource, underpinned by the best data and world-leading experts in the use of the best chemical probes for the study of particular proteins. The new developments on the Portal will now further improve the selection and use of the best tools available for experimental research and thus increase the quality and robustness of biomedical research.”