title: CDK2/cyclinA inhibitors: targeting the cyclinA recruitment site with small molecules derived from peptide leads.
abstract: The syntheses of potent small molecule inhibitors of the CDK2/cyclinA recruitment site are described. Structure-activity trends of nanomolar octapeptides were examined through amino-acid substitution and truncation of the sequence resulting in the identification of a smaller, albeit significantly less potent, tetrapeptide lead. These losses in affinity were recovered by side-chain optimization and by rigidification of the peptide backbone using a combination of solid-phase parallel synthesis and structure-based design. Finally, two guanidine functionalities were replaced to improve drug-like properties, resulting in neutral small molecules equal in activity to that of the peptide lead.
authors.affiliation: Department of Medicinal Chemistry, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Georgette
authors.initials: G
authors.lastname: Castanedo
authors.forename: Kevin
authors.initials: K
authors.lastname: Clark
authors.forename: Shumei
authors.initials: S
authors.lastname: Wang
authors.forename: Vickie
authors.initials: V
authors.lastname: Tsui
authors.forename: Mengling
authors.initials: M
authors.lastname: Wong
authors.forename: John
authors.initials: J
authors.lastname: Nicholas
authors.forename: Dineli
authors.initials: D
authors.lastname: Wickramasinghe
authors.forename: James C
authors.initials: JC
authors.lastname: Marsters
authors.forename: Daniel
authors.initials: D
authors.lastname: Sutherlin
mesh_terms: D019943:Amino Acid Substitution; D019925:Cyclin A / Q000037:antagonists & inhibitors* / Q000737:chemistry; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D019791:Guanidine / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation
chemical_list: D019925:Cyclin A; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D051357:Cyclin-Dependent Kinase 2; D019791:Guanidine