title: EC144 is a potent inhibitor of the heat shock protein 90.
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.
authors.affiliation: Biogen Idec, 5200 Research Place, San Diego, California 92122, USA.
authors.forename: Jiandong
authors.initials: J
authors.lastname: Shi
authors.forename: Ryan
authors.initials: R
authors.lastname: Van de Water
authors.forename: Kevin
authors.initials: K
authors.lastname: Hong
authors.forename: Ryan B
authors.initials: RB
authors.lastname: Lamer
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Weichert
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Sandoval
authors.forename: Srinivas R
authors.initials: SR
authors.lastname: Kasibhatla
authors.forename: Marcus F
authors.initials: MF
authors.lastname: Boehm
authors.forename: Jianhua
authors.initials: J
authors.lastname: Chao
authors.forename: Karen
authors.initials: K
authors.lastname: Lundgren
authors.forename: Noelito
authors.initials: N
authors.lastname: Timple
authors.forename: Rachel
authors.initials: R
authors.lastname: Lough
authors.forename: Gerardo
authors.initials: G
authors.lastname: Ibanez
authors.forename: Christina
authors.initials: C
authors.lastname: Boykin
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Burrows
authors.forename: Marilyn R
authors.initials: MR
authors.lastname: Kehry
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Yun
authors.forename: Erin K
authors.initials: EK
authors.lastname: Harning
authors.forename: Christine
authors.initials: C
authors.lastname: Ambrose
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Thompson
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Bixler
authors.forename: Anthone
authors.initials: A
authors.lastname: Dunah
authors.forename: Pamela
authors.initials: P
authors.lastname: Snodgrass-Belt
authors.forename: Joseph
authors.initials: J
authors.lastname: Arndt
authors.forename: Istvan J
authors.initials: IJ
authors.lastname: Enyedy
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.forename: Victor S
authors.initials: VS
authors.lastname: Hong
authors.forename: Andres
authors.initials: A
authors.lastname: McKenzie
authors.forename: Marco A
authors.initials: MA
authors.lastname: Biamonte
mesh_terms: D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D014961:X-Ray Diffraction
chemical_list: C555354:EC 144; D018841:HSP90 Heat-Shock Proteins; D011743:Pyrimidines; D011758:Pyrroles