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 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.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Shi J,Van de Water R,Hong K,Lamer RB,Weichert KW,Sandoval CM,Kasibhatla SR,Boehm MF,Chao J,Lundgren K,Timple N,Lough R,Ibanez G,Boykin C,Burrows FJ,Kehry MR,Yun TJ,Harning EK,Ambrose C,Thompson J,Bixler SA,Dunahdoi
10.1021/jm300810xsubject
Has Abstractpub_date
2012-09-13 00:00:00pages
7786-95issue
17eissn
0022-2623issn
1520-4804journal_volume
55pub_type
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