The central hypothesis of this proposal is that protein-protein interactions can be replicated or disrupted by stabilized peptides that have been identified via the identification of pharmacophores of small peptides that interact with CDK4/6. The basis for this hypothesis is formed by preliminary data generated by this lab that demonstrates small molecule inhibition of CDK4/6 can be achieved by applying peptide-based structure-function studies for pharmacophore identification. The rationale for the research project is that stabilized peptides derived from these pharmacophores can be identified and evaluated on a faster basis than de novo synthesis of a series of compounds.
The researchers are determining structure-function relationships of overlapping peptides derived from p16INK4a that inhibit the activity of CDK4/6 and identifying stabilized peptides that inhibit CDK4/6. The pharmacophore(s) of mutated peptides from p16INK4a will be assessed via time-resolved fluorescent resonance energy transfer assays and nuclear magnetic resonance spectroscopy to elucidate which residues are important to bind CDK4 and/or CDK6. Stabilized peptides will be evaluated for inhibitory activity toward CDK4/6. Experimental studies can then be used to evaluate the stabilized peptides for "drug-like" qualities.