Dr Domenico Sanfelice, Chemical Biology Curator at The Institute of Cancer Research, London and the Portal Curator, looks back at recent updates to the Portal including interesting small molecules, new protein targets and changes to the Chemical Probes Portal.

It’s been a busy year here at the Chemical Probes Portal. We’ve built a new Portal website, released 115 new compounds and published 212 new expert reviews. We have added 80 new protein targets including new, interesting molecules like PROTACs, molecular glues and degraders – as well as more conventionally-acting inhibitors and agonists – in our selection of small molecules.

Our aims for the Portal – to extend the number of high-quality chemical probes, increase the number of proteins for which high-quality chemical probes are available, and encourage the use of the best chemical tool compounds – are exemplified in some of the outstanding new molecules added this year.

New compounds

STM2457 is a first-in-class compound inhibiting the METTL3 methyltransferase. METTL3 complexes with METTL14 to catalyse N6-methyladenosine RNA modifications, which are linked to acute myeloid leukaemia. STM2457 is a highly selective inhibitor for METTL3, showing no inhibitory effect on other RNA methyltransferases or on a panel of 468 kinases.

Adding to the chemical toolbox, BI-3802 is a BCL6 degrader, providing some interesting comparisons between degrading and inhibiting this target with the BCL6 inhibitor BI-3812. Both are recommended for use by our expert reviewers, with the new BCL6 degrader receiving the highest, 4-star, rating.

Many compounds added to the Portal in recent months target proteins for which chemical probes were not previously available – including AS-99, a first-in-class inhibitor of ASH1L.

In total, we added 80 new protein targets to the Portal in 2021. The challenge as always is to find high-quality compounds that can work as chemical probes for understudied new targets, as well as recently available best-in-class probes for well-characterised proteins.

Evaluating probes for new targets continue to be our focus for 2022, mirroring other global drug discovery initiatives that aim to find new probes for targets lacking high-quality chemical tools – such as the efforts led by our good friends at Target2035. If there’s a new chemical probe you want to see on the Portal, or a protein target you think we should feature, please use our new user-friendly submission system or contact us with your request.

A year of reviews

Thank you to the many members of our Scientific Expert Review Panel (SERP) for another busy year of reviews. We have continued to grow the numbers of experts who review compounds, with 200 SERP members reviewing 212 times in 2021.

Our expert reviewers provide invaluable advice about using probes in biological experiments – including factors to be considered and warnings. For example, while many compounds have superior potencies, their activity might not have been profiled against a wide range of other targets.

For example, IMP-1088 is an excellent compound added this year. Kallemeijn et al have done a great job assessing its selectivity against other members of the acetyltransferase family. But the profiling isn’t complete, as one other reviewer has mentioned – our knowledge of its broader activity could be improved by adding data on its selectivity outside the immediate acetyltransferase enzyme family.

And building on the theme of acknowledging the caveats to using even well-chosen chemical probes, the Portal is increasingly home to sophisticated information that will help users in experimental design. Some compounds, for example, are useful as orthogonal controls: a second compound of a different chemical structure to use alongside a chemical probe to confirm your results. See for example the free fatty acid receptor FFAR1 chemical probe AMG-837 for a good example.

And finding the right chemical probe is only part of the problem we are trying to address. Even the best probe can provide misleading results if used at the wrong concentration. But as always, our reviewers have provided many helpful comments about how to use chemical probes effectively (e.g. for Entospletinib), including the appropriate concentration for use in vitro and the dose to give in animal experiments, for example, IMP-1710. See the reviewer recommended concentration on the probe page – which, when available, may supersede the previous value for a given probe on the Portal.

The New Portal

No look at the past year would be complete without sharing some thoughts on our new version of the Portal. The new site has significantly improved the user and reviewer experience, with new online forms for submitting and reviewing compounds. A new backend structure has as transformed the speed with which we can add compounds and reviews to the Portal.

For the coming year, we are designing new functionality to further enhance the visualisation and user experience. We are also working in collaboration with the Probe Miner resource to suggest new probes that should be added to the Portal, as well as with the canSAR team to enable rapid and automatic gathering of data about compounds. You can find details on all the updates to the new site here.

We’ve worked hard to make the new system easier to use, with a quicker search function and improved results. We’re still keen to hear your feedback so that we can make the platform as easy to use, and as helpful, as possible.

A huge thank you to our supporters, funders, reviewers and users. It’s your hard work and dedication to the best science that makes this community resource a success. I’m looking forward to adding many new compounds and reviews to the Portal in 2022, and making this resource as helpful for the research community as it can be.

From the Curator – an exciting time for the Chemical Probes Portal