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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on November 14, 2003; DOI: 10.1124/jpet.103.059568

0022-3565/04/3083-814-819$20.00
JPET 308:814-819, 2004
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CELLULAR AND MOLECULAR

Xylocydine, a Novel Inhibitor of Cyclin-Dependent Kinases, Prevents the Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand-Induced Apoptotic Cell Death of SK-HEP-1 Cells

Young-Mi Ham, Kyoung-Jin Choi, Sun-Yong Song, Ying-Hua Jin, Moon-Woo Chun, and Seung-Ki Lee

Division of Pharmaceutical Biosciences, College of Pharmacy, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea (Y.-M.H., K.-J.C., Y.-H.J., S.-K.L.); and Department of Medicinal Chemistry, College of Pharmacy, Seoul National University, Seoul, Korea (S.-Y.S., M.-W.C.)

Xylocydine (4-amino-6-bromo-7-({beta}-L-xylofuranosyl)pyrrolo[2,3-d]pyrimidine-5-carboxamide) blocks cyclin-dependent kinase CDK1 and CDK2/cyclin A activity in vitro (IC50 1.4 and 61 nM, respectively) while minimally inhibiting the three other Ser/Thr protein kinases tested (IC50 21–86 µM). Reduced phosphorylated nucleolin and retinoblastoma protein levels showed it also efficiently inhibited cellular CDK1 and CDK2 activity (IC50 50–100 and 200–500 nM, respectively). Moreover, it blocked the functional activity of CDKs in tumor necrosis factor-related apoptosis-inducing ligand-induced SK-HEP-1 cell apoptosis 20 to 1000-fold more potently than olomoucine and roscovitine. Xylocydine is thus a novel and potent CDK inhibitor that could be used to interfere with cell cycle- and apoptosis-related CDK activity in various diseases.

Received for publication September 3, 2003
Accepted November 10, 2003.

Address correspondence to: Dr. Seung-Ki Lee, Division of Pharmaceutical Biosciences, College of Pharmacy, Seoul National University, San 56–1, Shillim-Dong, Kwanak-Gu, Seoul, 151–742, Korea. E-mail: sklcrs{at}plaza.snu.ac.kr






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