The Chemical Probe Portal is a free online resource to help scientists find and use high-quality chemical probes in biomedical research and drug discovery. It is a major initiative of the international expert chemical probe community, which is seeking to increase the use of better quality chemical probes in experimental studies around the world and to promote best practices to improve the robustness of biomedical research.
Chemical probes are very well characterized, usually inhibitory, small molecules that affect the activity of a specific protein target. They are often used in biological research, for example to study target protein function 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 number of criteria are used to evaluate the quality of chemical probes. A particularly important property is the selectivity of a chemical probe, i.e. the preferential action of the probe against the predicted protein with respect to other proteins of the same family and also other unrelated protein families.
With a well-characterized, broad-profile chemical probe in hand and following best practice guidelines, a researcher can have greater confidence that the observed effects in cells or animals are actually the result of the expected protein modulation.
Originally established in 2015, the chemical probe portal was relaunched and updated in 2021, when the team opened its extensively rebuilt website, released 115 new probe compounds, and added more than 200 new expert reviews.
Portal’s team also added 80 new protein targets including, for the first time, those that act as PROTACs, molecular degraders and glues, as well as more traditional 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, 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, curator of chemical biology at the Cancer Research Institute, London.
The chemical probe portal was developed with support from organizations including the Structural Genomics Consortium (SGC), Cancer Research UK and most recently a major biomedical research grant from Wellcome. Now housed at the ICR, the Portal is supported by the work of approximately 200 active medical chemistry, chemical biology and drug discovery experts from around the world, contributing expert reviews and guidance on the use of each loaded probe.
The expert review process is part of what makes the portal unique, explains Dr Susanne Müller-Knapp, director of operations of the portal and chief operating officer of the Structural Genomics Consortium, Frankfurt. “Three experts review each compound submitted to the Portal and assign it a star rating. We recommend that compounds with the highest ratings of three or four stars can be used as chemical probes to study their protein target.
“For a high quality probe, we want to see a very selective compound for the desired protein target, with broad selectivity within the protein family but also outside the family. We also need evidence of target involvement and activity within the cells. And we want to see researchers use these probes at the appropriate concentration in cells. Furthermore, for in vivo use, which most commonly means mouse models, we also need to see acceptable pharmacokinetic and pharmacodynamic data, as well as information on the appropriate dose. “
“For best practice, we also suggest that 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 that include genetic knockdown of the protein target if possible. “.
Improve quality and robustness
Chemical probes represent one of the major research interests of Professor Paul Workman, who is the Harrap Professor of Pharmacology and Therapy at the ICR and Executive Director of the Portal.
Professor Workman said, “With the Chemical Probe Portal, our goal is to provide the broader research community with an easily accessible resource, supported by the assessments of the world’s leading experts in using the best chemical probes to study. Equally 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 recently improved Portal will increase the selection and use of the best chemical tools available and, in so doing, help increase the quality and robustness of biomedical research.
‘It takes years of work to get a really good, well-characterized quality probe,’ continues Professor Workman. “In the past, compounds emerging from chemical screens have been used as chemical probes when they have not undergone sufficient chemical optimization or a detailed mechanistic biological profile. Many compounds that continue to be used as chemical probes are, frankly, promiscuous compounds that should never be used – or they may simply have one or some particular off-target effects that will need to be considered in a given experimental context. Note also that chemical probes evolve over time, with compounds being useful as initial explorers eventually being replaced by more selective chemical probes.
“We want to give researchers access to up-to-date expert advice so that they use only the best chemical probes in their research and are aware of any applicable limitations.”
One of the major updates from the previous iteration of the Portal is a new ability to sift through huge datasets, suggesting interesting compounds to consider as probes for later expert analysis. Data sources include ICR’s canSAR, the world’s largest public resource for cancer drug discovery, and ICR’s Probe Miner, a leading community resource for the objective evaluation of chemical probes based on medical chemistry data , large-scale pharmacology and chemical biology.
Professor Bissan Al-Lazikani, former chief of data science at the ICR and now professor of genomic medicine at MD Anderson Cancer Center in Houston, is director of informatics and technologies on the portal’s leadership team. He says, “While expert peer review remains the fundamental basis for the Portal’s evaluation and recommendation of chemical probes, we also want to ensure that both our expert reviewers and the wider research community benefit from access to a distillation. the sheer volume of data and tools that provide objective analysis to complement the peer review assessment. “
In the coming year, the Chemical Probe Portal team aims to add more compounds for more targets and more expert reviews, as well as promote greater awareness of its transformational potential on international research, including through a series of communications targeting the biological community. international.
“Selecting good compounds is really important, but also difficult, and this is where the Portal comes into play. You have a ready-made set of selective tools with helpful comments from expert reviewers on how to best use them. We need to get the word out: Better compound choice leads to better science and more solid results. ”Says Dr. Ben Bellenie, Senior Staff Scientist on ICR’s Medicinal Chemistry Team 4 and member of the Portal’s Scientific Expert Review Panel.
‘The aim is to increase the number of high-quality compounds used in biomedical research by providing up-to-date information on the quality of chemical probes,’ explains Professor Workman.
“The Portal is already used by 1,500 visitors per month all over the world. But we have yet to get the message out more broadly, particularly to the biological research community that uses chemical probes. There continue to be many examples where the use of poor reagents results in wrong conclusions in publications and wrong decisions are made in drug discovery and development. “Says Professor Workman.” That’s why we have an active communication and awareness program aimed at laboratory researchers, journal editors and grant funders, and we are working closely with the Target 2035 initiative which aims to discover probes for the entire human proteome.
“I highly recommend using the Portal for your own research and when reviewing documents or experimental research, and I also encourage 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 is a new chemical probe you want to see on the Portal, or a protein target that you think we should introduce, please let us know. If you are a principal investigator or senior researcher, please consider joining our roster of expert reviewers. And if you have any questions about chemical probes or the Portal, please get in touch with any team member or through the website! “
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