We aim to identify small molecules that inhibit novel protein targets in mitosis, an area of biology that is deeply relevant to cancer. We will focus on inhibitors of kinesin motor proteins since we know they are essential for mitosis and that they can be inhibited with small molecules. We recently identified a hit from a combinatorial library that inhibits a mitotic kinesin, Eg5, and we will optimize its affinity by synthesizing a library of related compounds. We will use phenotypic screens to identify protein targets through their sensitivity to small molecules; this will serve two purposes, identifying the protein as important in mitosis, and identifying it as a protein that is possible to target with small molecules. Both pieces of information are important for possible drug development efforts. We will screen for inhibitors of several mitotic kinesins using pure protein assays, including high throughput binding assays on small molecule microarrays. Inhibitors of mitotic kinesins will be characterized by enzymology using pure protein and tested for phenotypic effects on cells, then used to test concepts of mechanisms for selective cancer cell killing.
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