Chemical Probes

Why do we need high quality open access chemical probes?

Potent, selective and cell-permeable inhibitors of protein function ("chemical probes") are valued reagents in both fundamental and applied biological research, and they are essential for the early stages of drug discovery by allowing preclinical target validation in both academic and industrial laboratories. History shows that the pharmaceutical industry is far more likely to pursue a drug discovery programme if there are already well-characterised inhibitors with defined mechanisms of action available. However, chemical probes are not widely available because they are difficult to produce without access to skilled medicinal chemists; they are also frequently targeted to the relatively few proteins that have already been the focus of industrial drug discovery efforts and are often encumbered by intellectual property and restrictive material transfer agreements. Moreover, many of the probes currently available are inadequately characterized and nonselective, which can muddy the conclusions of experiments carried out by the research community.

One solution to this problem might be for industry to use their medicinal chemistry expertise to provide chemical probes for all potential drug targets. However, the decreasing productivity of industry requires them to apply more effort on later-stage drug development and to move away from target discovery. The situation has created a paradox: industry is increasingly dependent on academia to discover and validate new targets, yet target validation is optimally done with the use of well-characterized chemical probes, whose derivation is best done in industry.

Strategies for generating probes

Through strategic collaborations, we are applying a systematic approach to generating chemical probes for kinases and epigenetic proteins, building on the output of the SGC, which has produced most of these human proteins in purified form and has determined the three-dimensional structures of many. We have developed biophysical and biochemical assays that allow identification of hits and understanding of SAR (structure activity relationships). To generate and optimize small molecule hits, we make particular use of structure based design, including screening of fragments and selection of compound libraries based on protein family chemogenomics, in addition to high throughput screening of diversity libraries. Iterative improvement of potency and selectivity are accelerated by the family-wide availability of purified proteins at the SGC and the growing level of structural understanding of the protein families and their interactions with ligands.

Fig 1: Identification of fragments that displace histone peptides from bromodomains

Probe dissemination

In keeping with SGC policy, the structure and data associated with each probe will promptly be made freely available, using a web-based datasheet repository with live links to source data wherever possible. To ensure that the chemical probes will be used immediately and with maximal benefit, they will be treated as precompetitive reagents and made available to all researchers without restriction on use, avoiding the bureaucracy and lengthy delays that can occur when interinstitutional material transfer agreements need to be set up.