title: Discovery and initial characterization of the paullones, a novel class of small-molecule inhibitors of cyclin-dependent kinases.
abstract: Analysis of the National Cancer Institute Human Tumor Cell Line Anti-Cancer Drug Screen data using the COMPARE algorithm to detect similarities in the pattern of compound action to flavopiridol, a known inhibitor of cyclin-dependent kinases (CDKs), has suggested several possible novel CDK inhibitors. 9-Bromo-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one, NSC-664704 (kenpaullone), is reported here to be a potent inhibitor of CDK1/cyclin B (IC50, 0.4 microM). This compound also inhibited CDK2/cyclin A (IC50, 0.68 microM), CDK2/cyclin E (IC50, 7.5 microM), and CDK5/p25 (IC50, 0.85 microM) but had much less effect on other kinases; only c-src (IC50, 15 microM), casein kinase 2 (IC50, 20 microM), erk 1 (IC50, 20 microM), and erk 2 (IC50, 9 microM) were inhibited with IC50s less than 35 microM. Kenpaullone acts by competitive inhibition of ATP binding. Molecular modeling indicates that kenpaullone can bind in the ATP binding site of CDK2 with residue contacts similar to those observed in the crystal structures of other CDK2-bound inhibitors. Analogues of kenpaullone, in particular 10-bromopaullone (NSC-672234), also inhibited various protein kinases including CDKs. Cells exposed to kenpaullone and 10-bromopaullone display delayed cell cycle progression. Kenpaullone represents a novel chemotype for compounds that preferentially inhibit CDKs.
authors.affiliation: Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland 20892-7444, USA. zaharevitz@dtpax2.ncifcrf.gov
authors.forename: D W
authors.initials: DW
authors.lastname: Zaharevitz
authors.forename: R
authors.initials: R
authors.lastname: Gussio
authors.forename: M
authors.initials: M
authors.lastname: Leost
authors.forename: A M
authors.initials: AM
authors.lastname: Senderowicz
authors.forename: T
authors.initials: T
authors.lastname: Lahusen
authors.forename: C
authors.initials: C
authors.lastname: Kunick
authors.forename: L
authors.initials: L
authors.lastname: Meijer
authors.forename: E A
authors.initials: EA
authors.lastname: Sausville
mesh_terms: D000465:Algorithms; D001552:Benzazepines / Q000737:chemistry* / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects*; D002478:Cells, Cultured / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D005419:Flavonoids / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology; D008956:Models, Chemical; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D001552:Benzazepines; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007211:Indoles; D010880:Piperidines; C119620:kenpaullone; C077990:alvocidib; D018844:Cyclin-Dependent Kinases