| Autor: |
Brooks, Eric E., Gray, Nathanael S., Joly, Alison, Kerwar, Suresh S., Lum, Robert, Mackman, Richard L., Norman, Thea C., Rosete, Jose, Rowe, Michael, Schow, Steven R., Schultz, Peter G., Wang, Xingbo, Wick, Michael M., Shiffman, Dov |
| Zdroj: |
Journal of Biological Chemistry; November 1997, Vol. 272 Issue: 46 p29207-29211, 5p |
| Abstrakt: |
The activity of cyclin-dependent kinase 2 (CDK2) is essential for progression of cells from G1to the S phase of the mammalian cell cycle. CVT-313 is a potent CDK2 inhibitor, which was identified from a purine analog library with an IC50of 0.5 μmin vitro. Inhibition was competitive with respect to ATP (Ki= 95 nm), and selective CVT-313 had no effect on other, nonrelated ATP-dependent serine/threonine kinases. When added to CDK1 or CDK4, a 8.5- and 430-fold higher concentration of CVT-313 was required for half-maximal inhibition of the enzyme activity. In cells exposed to CVT-313, hyperphosphorylation of the retinoblastoma gene product was inhibited, and progression through the cell cycle was arrested at the G1/S boundary. The growth of mouse, rat, and human cells in culture was also inhibited by CVT-313 with the IC50for growth arrest ranging from 1.25 to 20 μm. To evaluate the effects of CVT-313 in vivo, we tested this agent in a rat carotid artery model of restenosis. A brief intraluminal exposure of CVT-313 to a denuded rat carotid artery resulted in more than 80% inhibition of neointima formation. These observations suggest that CVT-313 is a promising candidate for evaluation in other disease models related to aberrant cell proliferation. |
| Databáze: |
Supplemental Index |
| Externí odkaz: |
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