Biogen Idec, 5200 Research Place, San Diego, California 92122, USA.
J Med Chem. 2012 Sep 13;55(17):7786-95. doi: 10.1021/jm300810x. Epub 2012 Aug 31.
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.
炔烃 40，5-（2-氨基-4-氯-7-（（4-甲氧基-3,5-二甲基吡啶-2-基）甲基）-7H-吡咯并[2,3-d]嘧啶-5-基）-2-甲基戊-4-炔-2-醇（EC144），是第二代热休克蛋白 90（Hsp90）抑制剂，其体外和体内活性均明显强于完成 II 期临床试验的第一代抑制剂 14（BIIB021）。炔烃 40 在 Hsp90α 结合测定（IC50 = 1.1 vs 5.1 nM）以及在 MCF-7 细胞中降解 Her-2 的能力方面均强于 14（EC50 = 14 vs 38 nM）。在 N87 胃肿瘤小鼠模型中，40 以 5mg/kg 剂量可阻止肿瘤生长，并以 10mg/kg（po，qd×5）剂量引起部分肿瘤消退。在相同条件下，14 仅在 120mg/kg 剂量时可阻止肿瘤生长，且不诱导部分消退。因此，炔烃 40 在小鼠中的效力约比 14 强 20 倍。
