Dynamic modulators: Novel effectors of NF-kappaB signalling

NF κ B通路被广泛认为是多种重要细胞过程的关键，包括增殖和凋亡。它相应地涉及多种病理，例如癌症和炎症性疾病。在最近的工作中（例如纳尔逊，D. E、Ihekwaba，A. E. C.的方法，埃利奥特，M.，吉布尼角一、福尔曼，B。E、纳尔逊，G.，你看小维霍顿角一、Spiller，D. G.，爱德华兹，S。W.，McDowell，H. P.，尤尼特，J.F.，Sullivan，E.，格里姆利河，Benson，N.，Broomhead，D.美国，Kell，D. B。&白色，M. R. H.（2004年）。NF-κ B信号的振荡控制靶基因表达的动力学。Science 306，704-708），我们已经表明NF κ B中的信号传导可能不是通过NF κ B本身的幅度的调制而是通过其频率或动力学的调制来操作。因此，我们需要能够调节这些差异的工具，化学基因组学为获得它们提供了令人兴奋的前景。一组重要的此类工具以小（药物样）分子为代表，一个有用的策略是筛选具有所需活性的分子的文库。当我们获得了我们所需要的具有活性的“命中物”时，我们将在计算机中研究它们的结构和性质，以便在“实际上”更大的可用分子库中筛选具有适当化学相似性的物质，然后也筛选这些物质。这将导致分子具有更高的效力，从而具有更高的特异性。这些将通过合成变异体并再次测试它们来进一步改进。最有效的分子（具有最高亲和力的那些）将被固定在柱上，并用于钓出它们所结合的靶标，从而允许鉴定靶标。这种策略的吸引人的特征是（i）我们不需要知道首先影响动力学所必需的“靶标”，（ii）靶标可以来自任何途径，（iii）我们可以在细胞网络的相当“遥远”的区域中发现靶标，这些区域甚至不知道或不认为与NF κ B途径在功能上相互作用，（iv）我们因此获得一系列可以调节生物信号通路的动力学的试剂。

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.