Marked small molecule libraries: a truncated approach to molecular probe design

Screening small molecule libraries can be an effective way to find new drug candidates. However, identifying the cellular target of the active compound has traditionally meant re-synthesising the molecule to incorporate a tag, such as radio- or fluorescent label. Alison Hulme and colleagues at the University of Edinburgh have now come up with a new approach - by screening molecules that already incorporate linkers, any 'hits' can quickly have a tag attached to identify the target. Hulme answers OBC's questions below: 

1.     Could you briefly explain the focus of your article to the non-specialist?

Chemical genetics has been hailed as a new direction in drug discovery. But translating hits from screening large compound libraries into new druggable targets is still a difficult and time-consuming process. [We have developed] a new and widely applicable approach, focusing on the rapid development of molecular probes from library hits. Active molecular probes generated using this methodology can then be used in the target identification process.

2.     What is your particular interest in this area of research?

The antibiotic anisomycin is an activator of the stress activated protein kinase pathways, which play an important role in conditions such as ischemic brain injury resulting from stroke episodes, cancer and Alzheimer's disease. We have developed a small compound library based around the anisomycin core. However, finding the unknown cellular target of this compound and hence elucidating its mode of action has proved much more challenging. In order to address this problem we required a rapid synthesis of a range of biologically active molecular probes. For this reason we have chosen to mark compounds in our library with a small bio-compatible marker which might be readily homologated to give molecular probes, but which is inactive in cellular assays.

3.     Where do you see this field developing in the future?

The post-genome development of "omics" technologies means that it is now possible to carry out a detailed, molecular level screen for the effects of a drug, e.g. on gene expression. However, for the potential of these technologies to be realised and new drug candidates to be developed, a detailed knowledge of the biological target is required. Building in a small biocompatible marker to compound libraries might allow the screen-to-molecular-probe development process to be rapidly accelerated without adversely affecting the library results. 

4.     Are there any particular challenges facing future research in this area?

Finding the molecular target of active hits from chemical genetics screens is likely to throw up both the known unknowns (targets which might be expected to give rise to an observed phenotype) but might also illuminate unknown unknowns - the things which we didn't know that we didn't know before! Which of course is interesting, challenging and exciting.

James Mitchell Crow