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Crystal structures of human HSP90alpha-complexed with dihydroxyphenylpyrazoles.

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.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

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

doi

10.1016/j.bmcl.2004.12.087

subject

Has Abstract

pub_date

2005-03-01 00:00:00

pages

1475-8

issue

5

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(05)00005-3

journal_volume

15

pub_type

杂志文章

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