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ID: ALA1144366
Journal: Bioorg Med Chem Lett
Title: Crystal structures of human HSP90alpha-complexed with dihydroxyphenylpyrazoles.
Authors: Kreusch A, Han S, Brinker A, Zhou V, Choi HS, He Y, Lesley SA, Caldwell J, Gu XJ.
Abstract: 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.
CiteXplore: 15713410