- EC144 is a potent inhibitor of the heat shock protein 90
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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 (IC50 = 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.
- Shi, Jiandong,Van De Water, Ryan,Hong, Kevin,Lamer, Ryan B.,Weichert, Kenneth W.,Sandoval, Cristina M.,Kasibhatla, Srinivas R.,Boehm, Marcus F.,Chao, Jianhua,Lundgren, Karen,Timple, Noelito,Lough, Rachel,Ibanez, Gerardo,Boykin, Christina,Burrows, Francis J.,Kehry, Marilyn R.,Yun, Theodore J.,Harning, Erin K.,Ambrose, Christine,Thompson, Jeffrey,Bixler, Sarah A.,Dunah, Anthone,Snodgrass-Belt, Pamela,Arndt, Joseph,Enyedy, Istvan J.,Li, Ping,Hong, Victor S.,McKenzie, Andres,Biamonte, Marco A.
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supporting information
p. 7786 - 7795
(2012/11/07)
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- ALKYNYL PYRROLOPYRIMIDINES AND RELATED ANALOGS AS HSP90-INHIBITORS
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Alkynyl pyrrolo[2,3-d]pyrimidines and related analogs are described and demonstrated to have utility as Heat Shock Protein 90 (HSP90) inhibiting agents used in the treatment and prevention of various HSP90 mediated disorders. Methods of synthesis and use of such compounds are also described and claimed.
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Page/Page column 84-85
(2010/11/24)
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