Download MendeleyEC144 Is a Potent Inhibitor of the Heat Shock Protein 90.
Shi, J., Van de Water, R., Hong, K., Lamer, R.B., Weichert, K.W., Sandoval, C.M., Kasibhatla, S.R., Boehm, M.F., Chao, J., Lundgren, K., Timple, N., Lough, R., Ibanez, G., Boykin, C., Burrows, F.J., Kehry, M.R., Yun, T.J., Harning, E.K., Ambrose, C., Thompson, J., Bixler, S.A., Dunah, A., Snodgrass-Belt, P., Arndt, J., Enyedy, I.J., Li, P., Hong, V.S., McKenzie, A., Biamonte, M.A.(2012) J Med Chem 55: 7786-7795
- PubMed: 22938030
- DOI: https://doi.org/10.1021/jm300810x
- Primary Citation of Related Structures:
3QDD - PubMed Abstract:
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 Hsp90¦Á 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 ¡Á 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.
Organizational Affiliation:
Biogen Idec, 5200 Research Place, San Diego, California 92122, USA.
