The Chemical Probes Portal: an enhanced public resource providing expert advice on chemical tools for cancer research

Background: Chemical probes, usually inhibitors, are essential tools to interrogate physiological and disease mechanisms and validate drug targets. However, to be useful, they must meet stringent criteria: evidence of potency, selectivity, cell permeability and target engagement/modulation and a ‘Pharmacological Audit Trail’. Unfortunately, researchers frequently rely on the historically biased literature or use search engines or vendor catalogues, thus unwittingly selecting tools that may not be fit-for-purpose or are outdated. This results in publication of erroneous results and also in incorrect decisions in drug discovery, wasting substantial time and resources. To help researchers select the best available tools, the Chemical Probes Portal (CPP; www.chemicalprobes.org) was established in 2015 as an independent, non-profit, online resource to curate, annotate, score and document the quality of chemical probes. Here, we describe its 2021 relaunch, enhancements in usability and content, and future plans. Results: Since 2021, a new enhanced version of the free, online site is available, with >750 compounds, acting on 390 targets across multiple protein families, featuring a range of chemical tools, including PROTACs and molecular glues. Probe assessment is based on reviews by a ∼200-member expert panel. The new Portal has a faster, more intuitive search and easier online forms for submitting/reviewing compounds. Reviewers now benefit from automated data input from canSAR (cansarblack.icr.ac.uk), based on the medchem, pharmacology and chemical biology literature plus data from other peer-reviewed sources. The CPP also links to the complementary Probe Miner objective assessment resource (probeminer.icr.ac.uk). The new Portal features an entirely new database and backend structure to facilitate future updates. We provide new information pages, including guidelines and criteria for choosing/using well-validated compounds, e.g., guidelines for the characterization of probes for use in animals, where suitable PK/PD properties are needed. We emphasize how best practice includes use of probes from ≥2 different chemical classes (chemotypes) acting on the same protein as well as inactive control compounds, thus mitigating risk of off-target effects. We provide a useful section on ‘Historical Compounds’ which highlights those compounds that have been superseded or are otherwise unsuitable for use as chemical probes. Conclusion: The CPP is an invaluable community resource, enabling cancer researchers to choose the best chemical tools for their experiments. We will continue to expand toward proteome-wide coverage. We are extending our reach and impact by working with researchers and journal editors, including presentations at conferences, articles, blogs, webinars and social media, collaborating closely with the Target 2035 initiative (www.target2035.net). Conflict of interest: Ownership: DS, AC, EV-F, IM, YC, IC, PW, BA-L and AAA are/were employees of The Institute of Cancer Research (ICR), which has a commercial interest in a range of drug targets. The ICR operates a Rewards to Inventors scheme whereby employees of the ICR may receive financial benefits following the commercial licensing of a project. EV-F, AAA, BA-L and PW have been instrumental in the creation/development of canSAR and/or Probe Miner. P.W. was instrumental in the creation of the Chemical Probes Portal. AAA is/was a consultant of Darwin Health. BA-L is an employee of MD Anderson Cancer Center which also operates a Reward to Inventors Scheme. BA-L declares commercial interest in Exscientia and Astra Zeneca. BA-L is/was a consultant/ scientific advisory board member for GSK, Open Targets, Astex Pharmaceuticals, Astellas Pharma and is an ex-employee of Inpharmatica Ltd. BA-L was instrumental in the creation of ChEMBL and is a Director of the non-profit Chemical Probes Portal. B.A.-L. is/was a consultant/scientific advisory board member for GSK, Open Targets, Astex Pharmaceuticals, and Astellas Pharma, and is an ex-employee of Inpharmatica Ltd. P.W. is a consultant/scientific advisory board member for Alterome Therapeutics, Astex Pharmaceuticals, Black Diamond Therapeutics, CV6 Therapeutics, NextechInvest Ltd, Nuvectis Pharma, Storm Therapeutics and Vividion Therapeutics, and holds stock in Alterome, Black Diamond, Chroma Therapeutics, NextInvest, Nuvectis and Storm and is also a non-executive director of Storm a board member and executive director of the non-profit Chemical Probes Portal and a former employee of AstraZeneca. P.W. has received research funding from Astex, Cyclacel Pharmaceuticals, Merck KGaA, Nuvectis, Piramed Pharmaceuticals, Sixth Element Capital/CRT Pioneer Fund and Vernalis. I.C. is/was a consultant to Epidarex LLP, AdoRx Therapeutics, and Enterprise Therapeutics, and is a director of the non-profit Chemical Probes Portal. I.C. has received research funding from Astex, Merck KGaA, Janssen Biopharma, Monte Rosa Therapeutics, and Sixth Element Capital/CRT Pioneer Fund. I.C. holds stock in Monte Rosa Therapeutics AG and is a former employee of Merck Sharp & Dohme.