Details

Autor(en) / Beteiligte

• 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

Titel

CVT-313, a Specific and Potent Inhibitor of CDK2 That Prevents Neointimal Proliferation

Ist Teil von

• The Journal of biological chemistry, 1997-11, Vol.272 (46), p.29207-29211

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

1997

Quelle

MEDLINE

Beschreibungen/Notizen

• The activity of cyclin-dependent kinase 2 (CDK2) is essential for progression of cells from G1 to 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 IC50 of 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 IC50 for 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.