Cyclin dependent kinases (cdk) are central to the orderly progression of the cell-cycle, a process that underlies most diseases of cell proliferation in the body, e.g. cancer. The long term objective of this study is to use our recent discoveries about how cdks recognize and associate with their substrates to design agents that will inhibit these kinases. Such agents will be useful both for therapeutic purposes in the treatment of cancers and other diseases of abnormal cell proliferation and for further investigations into the mechanism of cell cycle control. A few inhibitors of cdks have been reported, but all of them target the ATP binding site of the catalytic kinase subunit. Although the catalytic cdk subunit is responsible for interaction with both the substrate serine or threonine and the ATP that donates the phosphate, increasing evidence suggests that the regulatory cyclin subunit plays a critical role in the recognition of substrate. Specifically, a hydrophobic groove on the surface of the cyclin interacts with a degenerate sequence on the substrate called a """"""""cyclin-binding"""""""" Cy motif.
The first aim i s to map the distance and orientation of a functional Cy motif relative to the substrate serine in the catalytic site of the kinase, studies that will illuminate the structural requirements for designing bi-functional (""""""""double-headed"""""""") cdk inhibitors.
The second aim i s to screen for """"""""designer"""""""" Cy motif peptides that have higher affinity or narrower specificity (towards different cyclins) so as to obtain Cy-mimetic cdk inhibitors optimal for therapy.
The third aim i s to design and screen for inhibitors that will mimic Cy motifs and will enter cancer cells to inhibit cell proliferation (or promote apoptosis).
These aims will take advantage of how this critical cell-cycle regulator interacts with its substrates and develop reagents for selectively interfering with this process for therapeutic purposes.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Experimental Therapeutics Subcommittee 1 (ET)
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Knowlton, John R
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University of Virginia
Schools of Medicine
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