EC144 Is a Potent Inhibitor of the Heat Shock Protein 90

Alkyne <b>40</b>, 5-(2-amino-4-chloro-7-((4-methoxy-3,5-dimethylpyridin-2-yl)­methyl)-7<i>H</i>-pyrrolo­[2,3-<i>d</i>]­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 <b>14</b> (BIIB021) that completed phase II clinical trials. Alkyne <b>40</b> is more potent than <b>14</b> 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 (EC₅₀ = 14 vs 38 nM). In a mouse model of gastric tumors (N87), <b>40</b> stops tumor growth at 5 mg/kg and causes partial tumor regressions at 10 mg/kg (po, qd×5). Under the same conditions, <b>14</b> stops tumor growth only at 120 mg/kg, and does not induce partial regressions. Thus, alkyne <b>40</b> is approximately 20-fold more efficacious than <b>14</b> in mice