Researchers can now explore over 1000 compounds via the Chemical Probes Portal to uncover top-notch inhibitors and chemical tools for their biological studies. Among these, 490+ compounds are deemed ‘high-quality’ probes with three or more stars from reviewers, making them recommended for investigating particular protein targets of interest. Encompassing 530+ human protein targets including kinases, epigenetic proteins, GPCRs, and more, the compounds feature a range of protein modulators: activators, agonists, antagonists, as well as newer modalities – like covalent inhibitors, degraders, and molecular glues.

Around 250 compounds are labelled as Unsuitables, comprising outdated ones, nuisance compounds, or highly unselective ones unsuitable to be used as selective chemical probes. For instance, LY294002, once claimed to inhibit PI3 kinase, is now known to have many off-target effects, prompting the search for better-targeted compounds (e.g. leniolisib and BYL-719).

All listed probes undergo peer review by a 250-member Scientific Expert Review Panel for suitability in cellular and in vivo experiments. Those earning 3 or 4 stars are recommended for selective target protein studies. Examples include EZH2 inhibitors UNC1999 and GSK343, and KRAS inhibitors MRTX849 and AMG-510.

Expanding into targeted protein degradation, the Portal lists various PROTACs and molecular glues. Supporting novel degrader development, new compounds target E3 ligases like GID4, with PFI-7 inhibiting GID4 recommended for biochemical and cellular assays.

Compounds with other modes of action on the Portal includes activators, agonists, and antagonists. GSK1016790A, an agonist of TRPV4, and Fasiglifam, an agonist of FFAR1, highlight the diversity of targets investigated.

“It’s fantastic we have reached this milestone, both as a team and as the wider community” says Professor Paul Workman, Director of the Portal and Harrap Professor of Pharmacology and Therapeutics at the Institute of Cancer Research, London. “To have 500 high quality chemical probes that cover 400 protein targets shows how far we have come. A huge thank you to our Scientific Expert Review Panel and the chemical probe community for helping us. However, we still need new compounds against a much wider range of protein targets and we all need to work hard on that. We also need the community to use chemical probes according to best practice guidelines which we provide on the Portal. We hope that a wider range of researchers will start to use the best compounds to do outstanding, rigorous science and the result of that will be a better understanding of protein function and more effective drugs for a range of diseases.”

Working with Target 2035, we aim to identify probes or tools for every human target by 2035. The way ahead is still long, necessitating collaboration and contributions from the research community. Researchers are encouraged to submit new compounds for review, join the Scientific Expert Review Panel, or engage with the Target 2035 initiative to expedite chemical probe discovery.

The Chemical Probes Portal reaches 1000 compounds