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-NH(2) 1, in which the C-terminal phenylalanine residue was replaced by alpha and/or beta-modified variants, was synthesized using solid-phase chemistry. Both the L-threo-beta-hydroxy-phenylalanine (beta-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 D-threo-Pse derivatives also showed inhibitory activity.
School of Pharmaceutical Sciences, University of Nottingham, University Park, NG7 2RD, Nottingham, UK.
Gail E
GE
Atkinson
Angela
A
Cowan
Campbell
C
McInnes
Daniella I
DI
Zheleva
Peter M
PM
Fischer
Weng C
WC
Chan
D000595:Amino Acid Sequence; D042846:CDC2-CDC28 Kinases; D002851:Chromatography, High Pressure Liquid; D019925:Cyclin A / Q000037:antagonists & inhibitors* / Q000737:chemistry; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry
D019925:Cyclin A; D004791:Enzyme Inhibitors; D010455:Peptides; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases