Dynamic modulators: Novel effectors of NF-kappaB signalling

点击翻译按钮获取中文摘要

The NFkappaB pathway is widely recognised as crucial to a variety of important cellular processes including both proliferation and apopotosis. It is correspondingly implicated in a variety of pathologies such as cancer and inflammatory disease. In recent work (e.g. Nelson, D. E., Ihekwaba, A. E. C., Elliott, M., Gibney, C. A., Foreman, B. E., Nelson, G., See, V., Horton, C. A., Spiller, D. G., Edwards, S. W., McDowell, H. P., Unitt, J. F., Sullivan, E., Grimley, R., Benson, N., Broomhead, D. S., Kell, D. B. & White, M. R. H. (2004). Oscillations in NF-kappaB signalling control the dynamics of target gene expression. Science 306, 704-708), we have shown that signalling in the NFkappaB likely operates not by modulations in the amplitude of NFkappaB per se but in its frequency or dynamics. We therefore need tools that can modulate these differentially, and chemical genomics provides an exciting prospect for acquiring them. An important set of such tools is represented by small (drug-like) molecules, and a useful strategy is to screen libraries of them for molecules with the desired activities. As we obtain 'hits' that are active in the way we require we shall study their structures and properties in a computer so as to screen 'virtually' much larger libraries of available molecules for substances that have appropriate chemical similarities, and then screen these too. This will lead to molecules with higher potency and thus higher specificity. These will be improved still further by making variants synthetically and again testing them. The most potent molecules (those with the highest affinity) will be immobilised on a column and used to fish out the target(s) to which they bind, thus allowing the identification of the target(s). Attractive features of this strategy are that (i) we do not need to know the 'target' that is necessary to affect the dynamics in the first place, (ii) targets may come from any pathway, (iii) we may find targets in quite 'distant' areas of the cellular network that were not even known or considered to interact functionally with the NFkappaB pathway, (iv) we thereby acquire a series of reagents that can modulate the dynamics of biological signalling pathways.