3QDD

HSP90A N-terminal domain in complex with BIIB021

Summary for 3QDD

• Entry DOI: 10.2210/pdb3qdd/pdb
• Descriptor: Heat shock protein HSP 90-alpha, 6-chloro-9-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-9H-purin-2-amine (3 entities in total)
• Functional Keywords: atpase, chaperone-chaperone inhibitor complex, chaperone/chaperone inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P07900
• Total number of polymer chains: 1
• Total formula weight: 27058.68

Authors

Arndt, J.W.,Biamonte, M.A. (deposition date: 2011-01-18, release date: 2012-07-18, Last modification date: 2024-05-22)

Primary citation

Shi, J.,Van de Water, R.,Hong, K.,Lamer, R.B.,Weichert, K.W.,Sandoval, C.M.,Kasibhatla, S.R.,Boehm, M.F.,Chao, J.,Lundgren, K.,Timple, N.,Lough, R.,Ibanez, G.,Boykin, C.,Burrows, F.J.,Kehry, M.R.,Yun, T.J.,Harning, E.K.,Ambrose, C.,Thompson, J.,Bixler, S.A.,Dunah, A.,Snodgrass-Belt, P.,Arndt, J.,Enyedy, I.J.,Li, P.,Hong, V.S.,McKenzie, A.,Biamonte, M.A.
EC144 Is a Potent Inhibitor of the Heat Shock Protein 90.
J.Med.Chem., 55:7786-7795, 2012

PubMed 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.

PubMed: 22938030
DOI: 10.1021/jm300810x

Experimental method

X-RAY DIFFRACTION (1.79 Å)