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Crystal structures of human HSP90alpha-complexed with dihydroxyphenylpyrazoles.

Kreusch, Andreas, Han, Shulin, Brinker, Achim, Zhou, Vicki, Choi, Ha-Soon, He, Yun, Lesley, Scott, Caldwell, Jeremy and Gu, Xiang-Ju (2005) Crystal structures of human HSP90alpha-complexed with dihydroxyphenylpyrazoles. Bioorganic & Medicinal Chemistry Letters, 15 (5). pp. 1475-1478. ISSN 0960-894X


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.

Item Type: Article
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Additional Information: author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used
Keywords: Hsp90; Pyrazole; Dihydroxyphenylpyrazole; Co-crystal; 3D-structure; Structure based drug design
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Date Deposited: 14 Dec 2009 14:02
Last Modified: 31 Jan 2013 01:22


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