Discovery and initial characterization of the paullones, a novel class of small-molecule inhibitors of cyclin-dependent kinases

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-de pendent 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 (ke npaullone), is reported here to be a potent inhibitor of CDK1/cyclin B (IC5 0 0.4 mu M). This compound also inhibited CDK2/cyclin A (IC50 0.68 mu M), C DK2/cyclin E (IC50 7.5 mu M), and CDK5/p25 (IC50 0.85 mu M) but had much le ss effect on other kinases; only c-src (IC50 15 mu M), casein-kinase 2 (IC5 0 20 mu M), erk 1 (IC50 20 mu M), and erk 2 (IC50 9 mu M) were inhibited wi th IC(50)s less than 35 mu M. 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 i n the crystal structures of other CDK2-bound inhibitors, Analogues of kenpa ullone, in particular 10-bromopaullone (NSC-672234), also inhibited various protein kinases including CDKs, Cells exposed to kenpaullone and 10-bromop aullone display delayed cell cycle progression. Kenpaullone represents a no vel chemotype:for compounds that preferentially inhibit CDKs.