EC144 Is a Potent Inhibitor of the Heat Shock Protein 90
| Autor: | Victor Hong, Andres McKenzie, Jianhua Chao, Erin K Harning, Ping Li, Francis Burrows, Jiandong Shi, Rachel Lough, Theodore J. Yun, Marcus F. Boehm, Gerardo Ibanez, Ryan Lamer, Kenneth W Weichert, Christina Boykin, Anthone W. Dunah, Istvan J. Enyedy, Christine Ambrose, Noelito Timple, Ryan Van de Water, Marilyn R. Kehry, Marco A. Biamonte, Joseph Arndt, Jeffrey Thompson, Srinivas Rao Kasibhatla, Cristina M Sandoval, Karen Lundgren, Kevin Hong, Pamela A. Snodgrass-Belt, Sarah A. Bixler |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
chemistry.chemical_classification
biology Chemistry Ligand binding assay Phases of clinical research Alkyne Hsp90 Molecular biology In vitro Pyrimidines X-Ray Diffraction In vivo Heat shock protein Drug Discovery biology.protein Humans Molecular Medicine Pyrroles Gastric tumor HSP90 Heat-Shock Proteins |
| Zdroj: | Journal of Medicinal Chemistry. 55:7786-7795 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | Alkyne 40, 5-(2-amino-4-chloro-7-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylpent-4-yn-2-ol (EC144), is a second generation inhibitor of heat shock protein 90 (Hsp90) and is substantially more potent in vitro and in vivo than the first generation inhibitor 14 (BIIB021) that completed phase II clinical trials. Alkyne 40 is more potent than 14 in an Hsp90α binding assay (IC(50) = 1.1 vs 5.1 nM) as well as in its ability to degrade Her-2 in MCF-7 cells (EC(50) = 14 vs 38 nM). In a mouse model of gastric tumors (N87), 40 stops tumor growth at 5 mg/kg and causes partial tumor regressions at 10 mg/kg (po, qd × 5). Under the same conditions, 14 stops tumor growth only at 120 mg/kg, and does not induce partial regressions. Thus, alkyne 40 is approximately 20-fold more efficacious than 14 in mice. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|