Iterative Conversion of Cyclin Binding Groove Peptides into Druglike CDK Inhibitors with Antitumor Activity

The cyclin groove is an important
recognition site for substrates
of the cell cycle cyclin dependent kinases and provides an opportunity
for highly selective inhibition of kinase activity through a non-ATP
competitive mechanism. The key peptide residues of the cyclin binding
motif have been studied in order to precisely define the structure–activity
relationship for CDK kinase inhibition. Through this information,
new insights into the interactions of peptide CDK inhibitors with
key subsites of the cyclin binding groove provide for the replacement
of binding determinants with more druglike functionality through REPLACE,
a strategy for the iterative conversion of peptidic blockers of protein–protein
interactions into pharmaceutically relevant compounds. As a result,
REPLACE is further exemplified in combining optimized peptidic sequences
with effective N-terminal capping groups to generate more stable compounds
possessing antitumor activity consistent with on-target inhibition
of cell cycle CDKs. The compounds described here represent prototypes
for a next generation of kinase therapeutics with high efficacy and
kinome selectivity, thus avoiding problems observed with first generation
CDK inhibitors.