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[Cancer Research 59, 2566-2569, June 1, 1999]
© 1999 American Association for Cancer Research
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[Cancer Research 59, 2566-2569, June 1, 1999]
© 1999 American Association for Cancer Research

Advances in Brief

Discovery and Initial Characterization of the Paullones, a Novel Class of Small-Molecule Inhibitors of Cyclin-dependent Kinases1

Daniel W. Zaharevitz2, Rick Gussio, Maryse Leost, Adrian M. Senderowicz, Tyler Lahusen, Conrad Kunick, Laurent Meijer and Edward A. Sausville

Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland 20892-7444 [D. W. Z., R. G., A. M. S., T. L., E. A. S.]; Cell Cycle Group, Centre National de la Recherche Scientifique, 29680 Roscoff, Bretagne, France [L. M., M. L.]; and Institut für Pharmazie, Universität Hamburg, D20146 Hamburg, Germany [C. K.]

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 µM). This compound also inhibited CDK2/cyclin A (IC50, 0.68 µM), CDK2/cyclin E (IC50, 7.5 µM), and CDK5/p25 (IC50, 0.85 µM) but had much less effect on other kinases; only c-src (IC50, 15 µM), casein kinase 2 (IC50, 20 µM), erk 1 (IC50, 20 µM), and erk 2 (IC50, 9 µM) were inhibited with IC50s less than 35 µM. 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.




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Copyright © 1999 by the American Association for Cancer Research.