title: Iterative conversion of cyclin binding groove peptides into druglike CDK inhibitors with antitumor activity.
abstract: 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.
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina , Columbia, South Carolina 29208, United States.
authors.forename: Padmavathy Nandha
authors.initials: PN
authors.lastname: Premnath
authors.forename: Sandra N
authors.initials: SN
authors.lastname: Craig
authors.forename: Shu
authors.initials: S
authors.lastname: Liu
authors.forename: Erin L
authors.initials: EL
authors.lastname: Anderson
authors.forename: Asterios I
authors.initials: AI
authors.lastname: Grigoroudis
authors.forename: George
authors.initials: G
authors.lastname: Kontopidis
authors.forename: Tracy L
authors.initials: TL
authors.lastname: Perkins
authors.forename: Michael D
authors.initials: MD
authors.lastname: Wyatt
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Pittman
authors.forename: Campbell
authors.initials: C
authors.lastname: McInnes
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D016213:Cyclins / Q000737:chemistry* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D016213:Cyclins; D010455:Peptides; D047428:Protein Kinase Inhibitors; D018844:Cyclin-Dependent Kinases