) It has become evident in the last few years that normal cell functions and those associated with a cancerous state involve changes in the microscopic distribution of cellular constituents, in addition to their activity .Although considerable attention has been directed toward affecting the kinetic (i.e., time) properties of cancer-related targets, disruption of spatial control has largely been ignored. The overall goal of Project #2 is to design and implement """"""""smart"""""""" fluorescent-based assays suitable for high throughput screening of small molecules that will disrupt the spatial relationship of prototype cancer targets. We will focus on both cell cycle- and apoptosis-controlling targets and, thus, this Project will be well integrated with Projects #1 and 3of the NCDDG. We will use these smart assays to evaluate potential """"""""spatial modulators"""""""" obtained from the NCI chemical libraries and from combinatorial libraries produced by Core A. Our working hypothesis is that the spatial modulators (SP AMs ) identified by these assay systems will yield entirely novel classes of useful anticancer therapeutics.
The Specific Aims of our Project are: (1) To develop and implement screening assays for the identification of agents that will disrupt the spatial regulation of key cell cycle controlling phosphatases, namely Cdc25Band Cdc25C; (2) To develop and implement screening assays for the identification of agents that will disrupt the spatial regulation of a key cell cycle controlling kinase, namely Cdk1/cyclin B and; (3) To develop and implement screening assays for the identification of agents that will disrupt the spatial regulation of key anti-apoptotic controlling proteins, namely AKT/PKB and thioredoxin .
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