Crystal structures of human HSP90alpha-complexed with dihydroxyphenylpyrazoles.

Article Details


Kreusch A, Han S, Brinker A, Zhou V, Choi HS, He Y, Lesley SA, Caldwell J, Gu XJ

Crystal structures of human HSP90alpha-complexed with dihydroxyphenylpyrazoles.

Bioorg Med Chem Lett. 2005 Mar 1;15(5):1475-8.

PubMed ID
15713410 [ View in PubMed

A series of dihydroxyphenylpyrazole compounds were identified as a unique class of reversible Hsp90 inhibitors. The crystal structures for two of the identified compounds complexed with the N-terminal ATP binding domain of human Hsp90alpha were determined. The dihydroxyphenyl ring of the compounds fits deeply into the adenine binding pocket with the C2 hydroxyl group forming a direct hydrogen bond with the side chain of Asp93. The pyrazole ring forms hydrogen bonds to the backbone carbonyl of Gly97, the hydroxyl group of Thr184 and to a water molecule, which is present in all of the published HSP90 structures. One of the identified compounds (G3130) demonstrated cellular activities (in Her-2 degradation and activation of Hsp70 promoter) consistent with the inhibition of cellular Hsp90 functions.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
4-(1,3-Benzodioxol-5-Yl)-5-(5-Ethyl-2,4-Dihydroxyphenyl)-2h-Pyrazole-3-Carboxylic AcidHeat shock protein HSP 90-alphaKd (nM)680N/AN/ADetails
4-(1h-Imidazol-4-Yl)-3-(5-Ethyl-2,4-Dihydroxy-Phenyl)-1h-PyrazoleHeat shock protein HSP 90-alphaKd (nM)280N/AN/ADetails