A traditional approach to developing new drugs is to start with a specific target or pathway that has already been validated by successful therapeutic agents and to find new compounds that target the same enzyme or disrupt the same pathway. In cancer chemotherapy, tubulin has been validated as an anticancer drug target through the success of the spindle poisons (i.e. paclitaxel and vinblastine). In a broad sense, tubulin is a component of the pathway of mitosis. Our hypothesis is that this pathway can be exploited for anticancer therapy by drugs that target proteins other than tubulin. As part of a project to determine whether genomic instability that is the hallmark of cancer creates therapeutic opportunities, we carried out a large-scale drug screen in yeast to identify compounds that are differentially toxic to cells lacking the mitotic spindle assembly checkpoint- compounds that target mitosis. We focused on compounds that are active in mammalian cells including human cancer cell lines and that disrupt mitosis but do not interfere with microtubule dynamics. Our preliminary results support the hypothesis that other components of mitosis may be valid drug targets.
The Specific Aims of this application are to identify the drug targets in yeast and mammalian cells and to determine the optimal cellular context for differential toxicity.
Specific Aim 1 is to identify the drug targets using genetic screens in yeast. If successful, we should be able to identify the corresponding mammalian targets by sequence homology. Alternatively, in Specific Aim 2 we propose to identify the mammalian drug targets by a screen of human genes in yeast or by physical isolation of human drug-binding proteins. Mammalian target identification may be desirable even if we can identify the yeast targets.
In Specific Aim 3 we will correlate the sensitivity of human cancer cell lines to the mitosis-specific compounds with either molecular target data or DNA microarray data available from the NCI.
In Specific Aim 4 we will prepare a limited number of structural analogues for each mitosis-specific compound to determine SARs and to prepare reagents that will be needed for experiments described in Specific Aims 1 and 2. Through these convergent studies we hope to identify new mitosis-specific anticancer agents, their targets and the contexts in which these compounds are most effective.
| Spiegel, P Clint; Kaiser, Shari M; Simon, Julian A et al. (2004) Disruption of protein-membrane binding and identification of small-molecule inhibitors of coagulation factor VIII. Chem Biol 11:1413-22 |
