title: Potent inhibition of CDC2 kinase activity by the flavonoid L86-8275.
abstract: L86-8275 [(-) cis-5,7-dihydroxy-2-(2-chlorophenyl)-8[4-(3-hydroxy-1- methyl)-piperidinyl]-4H-benzopyran-4-one] directly inhibits immunoprecipitated Cdc2 kinase activity from G2/M synchronized MDA-MB-468 breast carcinoma cells and is at least 250-fold more potent than either quercetin or genistein. Purified sea-star Cdc2 kinase (IC50 = 0.5 microM) was inhibited with a similar potency to immunoprecipitated Cdc2 kinase from MDA-MB-468 cells (IC50 = 0.4 microM). This inhibition was competitive with respect to ATP (KiATP = 0.041 microM) and noncompetitive with respect to a synthetic peptide substrate, CDK1S1 (AAKAKKTPKKAKK-CONH2, KiCDK1S1 = 0.14 microM). These data suggest L86-8275 as a lead structure for the development of inhibitors of the cyclin-dependent kinases.
authors.affiliation: Laboratory of Biological Chemistry, National Cancer Institute, Bethesda, MD 20892.
authors.forename: M D
authors.initials: MD
authors.lastname: Losiewicz
authors.forename: B A
authors.initials: BA
authors.lastname: Carlson
authors.forename: G
authors.initials: G
authors.lastname: Kaur
authors.forename: E A
authors.initials: EA
authors.lastname: Sausville
authors.forename: P J
authors.initials: PJ
authors.lastname: Worland
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D001943:Breast Neoplasms; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors*; D005260:Female; D005419:Flavonoids / Q000494:pharmacology*; D016195:G2 Phase; D019833:Genistein; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D007529:Isoflavones / Q000494:pharmacology; D007700:Kinetics; D008938:Mitosis; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010455:Peptides / Q000138:chemical synthesis / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011794:Quercetin / Q000494:pharmacology; D013379:Substrate Specificity; D014407:Tumor Cells, Cultured
chemical_list: D005419:Flavonoids; D006131:Growth Inhibitors; D007529:Isoflavones; D010455:Peptides; D010880:Piperidines; C077990:alvocidib; D000255:Adenosine Triphosphate; D011794:Quercetin; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D016203:CDC2 Protein Kinase