| Autor: |
Pevarello, P., Brasca, M. G., Amici, R., Orsini, P., Traquandi, G., Corti, L., Piutti, C., Sansonna, P., Villa, M., Pierce, B. S., Pulici, M., Giordano, P., Martina, K., Fritzen, E. L., Nugent, R. A., Casale, E., Cameron, A., Ciomei, M., Roletto, F., Isacchi, A., Fogliatto, G., Pesenti, E., Pastori, W., Marsiglio, A., Leach, K. L., Clare, P. M., Fiorentini, F., Varasi, M., Vulpetti, A., Warpehoski, M. A. |
| Zdroj: |
Journal of Medicinal Chemistry; June 2004, Vol. 47 Issue: 13 p3367-3380, 14p |
| Abstrakt: |
Abnormal proliferation mediated by disruption of the normal cell cycle mechanisms is a hallmark of virtually all cancer cells. Compounds targeting complexes between cyclin-dependent kinases (CDK) and cyclins, such as CDK2/cyclin A and CDK2/cyclin E, and inhibiting their kinase activity are regarded as promising antitumor agents to complement the existing therapies. From a high-throughput screening effort, we identified a new class of CDK2/cyclin A/E inhibitors. The hit-to-lead expansion of this class is described. X-ray crystallographic data of early compounds in this series, as well as in vitro testing funneled for rapidly achieving in vivo efficacy, led to a nanomolar inhibitor of CDK2/cyclin A (N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(2-naphthyl)acetamide (41), PNU-292137, IC50 = 37 nM) with in vivo antitumor activity (TGI > 50%) in a mouse xenograft model at a dose devoid of toxic effects. |
| Databáze: |
Supplemental Index |
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