Development of Inhibitors That Selectively Disrupt Substrate Recognition by Cyclin-Dependent Kinases

摘要

Upregulation of cyclin/cdk activity and the resulting deregulation of the cell cycle is a common feature in the malignant transformation of breast epithelial cells and thus makes cyclin/cdks an attractive target for drug design. The long-term goal of our work is to develop inhibitors which inhibit cyclin/cdk activity by disrupting the interaction between cyclins and their substrates, an association that requires a sequence motif in the substrate termed a Cy motif. Cy or RXL motifs are general purpose motifs for the interaction of cellular factors with cyclins. Recent work in our laboratory has shown that these motifs are critical determinants of both substrate recognition and specificity and function by targeting molecules to particular cyclin/cdk complexes. During the first year of grant support, we have made significant advancements into understanding substrate recognition by cyclin-dependent kinases. This work provides the framework for the development of Cy motif- derived peptides and small compounds capable of inhibiting cyclin- dependent kinases.