As with many jobs that we have to do both in and out of work, it is important to have the right tools for the right job. However, many research efforts are being undermined by the quality of the tools employed – particularly when it comes to small molecule chemical tools. One of the major challenges when it comes to unravelling the complexities of the biology underpinning any disease is the ability to ask precise questions and to effectively test hypotheses– as both are entirely dependent on the quality of the reagents employed. Over the recent years, there has been a growth in the range of specific, available molecular biology reagents to control and quantify gene, transcript or protein production as well as an increased awareness of the need for quality control and rigorous experimental conditions to ensure that any data generated are meaningful. However, this vigilance has been less evident in the use of small molecule chemical ligands in target validation studies – and in particular, many groups have put their faith in molecules that are either reported in top peer-reviewed journals as being selective inhibitors, or are sold as such. This has led to many papers reporting findings which are fundamentally unsound, and leads to a cascade of wasted time and effort over many years. There are many challenges to be faced in initiating and prosecuting drug discovery projects and it is imperative that we do not make the journey any more difficult by using inappropriate tools in key validation studies.
Unfortunately, although the experienced community has done much to shout about this problem – both regarding the lack of reproducibility of published data (links to – http://www.nature.com/news/reproducibility-1.17552 and http://blogs.nature.com/news/2011/09/reliability_of_new_drug_target.html and http://www.reuters.com/article/us-science-cancer-idUSBRE82R12P20120328) and also the need for high quality chemical probes (http://www.nature.com/nchembio/journal/v11/n8/full/nchembio.1867.html and http://www.nature.com/nchembio/focus/chemicalprobes/index.html and http://www.nature.com/nchembio/journal/v6/n3/full/nchembio.296.html and http://pubs.acs.org/doi/abs/10.1021/acsmedchemlett.5b00032 and http://www.sciencedirect.com/science/article/pii/S1074552110001985), the wider problem of the continued use of sub-optimal molecules continues. There are many reasons why small molecule inhibitors might be non-specific, or indeed actually false positives, but the experience to understand these data often doesn’t reside in the groups that are needing to use the tools for complex disease / pathway mechanism studies.
To rise to this challenge, a new website has been created (http://www.chemicalprobes.org/) which aims to increase the quality and reproducibility of biomedical research using chemical probes.
The website contains fundamental information for the wider community on the properties required for a chemical probe, details on common pan-assay interference compounds (link – http://www.nature.com/news/chemistry-chemical-con-artists-foil-drug-discovery-1.15991) and recommended best practice covering the use of chemical probes in target validation experiments. Working behind the scenes at this new portal is a team of experienced scientists from across the globe that have enormous collective experience in the fields of assay technologies, medicinal chemistry, chemical biology, target validation and drug discovery & development. This team is systematically working through published ‘chemical probes’ and providing expert commentary on their suitability for use for both in vitro and in vivo experiments. The concept is still in its early phase – there are lots of probes already evaluated and their reviews are available for anyone to read – and many open calls are drawing in probes for a wide range of new target classes. Hopefully, with the support of both the user and reviewer communities, this effort will start to make a big impact on the quality of disease target validation and hence on the choice of early drug discovery projects in the future.
Blog written by Simon Ward