Abstract
Xylocydine (4-amino-6-bromo-7-(β-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.
Footnotes
-
ABBREVIATIONS: CDK, cyclin-dependent kinase; Ser/Thr kinase, serine/threonine kinase; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; DTT, dithiothreitol; PKA, protein kinase A; PKC, protein kinase C; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium; CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid; CKII, casein kinase II; PARP, poly(ADP-ribose) polymerase; CS, calf serum; Rb, retinoblastoma protein.
-
This work was supported by the National Research Laboratory Fund (M10104000129-02J000005910), the Ministry of Science and Technology, and by Grant R01-2000-000-00113-0 from the Basic Research Program of the Korea Science and Engineering Foundation.
-
DOI: 10.1124/jpet.103.059568.
- Received September 3, 2003.
- Accepted November 10, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|