| Autor: |
Arienti, K. L., Brunmark, A., Axe, F. U., McClure, K., Lee, A., Blevitt, J., Neff, D. K., Huang, L., Crawford, S., Pandit, C. R., Karlsson, L., Breitenbucher, J. G. |
| Zdroj: |
Journal of Medicinal Chemistry; March 2005, Vol. 48 Issue: 6 p1873-1885, 13p |
| Abstrakt: |
The discovery of a series of novel, potent, and highly selective inhibitors of the DNA damage control kinase chk2 is disclosed. Here we report the first SAR study around inhibitors of this kinase. High-throughput screening of purified human chk2 led to the identification of a novel series of 2-arylbenzimidazole inhibitors of the kinase. Optimization was facilitated using homology models of chk2 and docking of inhibitors, leading to the highly potent 2-arylbenzimidazole 2h (IC50 15 nM). Compound 2h is an ATP-competitive inhibitor of chk2 that dose dependently protects human CD4+ and CD8+ T-cells from apoptosis due to ionizing radiation. This work suggests that a selective small molecule inhibitor of chk2 could be a useful adjuvant to radiotherapy, increasing the therapeutic window of such treatment. |
| Databáze: |
Supplemental Index |
| Externí odkaz: |
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