Peptide inhibitors of CDK2-cyclin A that target the cyclin recruitment-Site: structural variants of the C-Terminal Phe

A focused series of octapeptides based on the lead compound H-His-Ala-Lys-Arg-Arg-Leu-Ile-Phe-NH21, in which the C-terminal phenylalanine residue was replaced by α and/or β-modified variants, was synthesized using solid-phase chemistry. Both the -threo-β-hydroxy-phenylalanine (β-phenylserine, Pse) and (2S)-phenylalaninol derivatives, as competitive binders at the cyclin-recruitment site, displayed potent inhibitory activity towards the CDK2-cyclin A complex. Unexpectedly, the -threo-Pse derivatives also showed inhibitory activity.