Crystal structures of human HSP90alpha-complexed with dihydroxyphenylpyrazoles
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 f...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2005-03, Vol.15 (5), p.1475-1478 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Kreusch, Andreas Han, Shulin Brinker, Achim Zhou, Vicki Choi, Ha-soon He, Yun Lesley, Scott A Caldwell, Jeremy Gu, Xiang-ju |
| description | 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. |
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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. 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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. 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| fulltext | fulltext |
| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2005-03, Vol.15 (5), p.1475-1478 |
| issn | 0960-894X |
| language | eng |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Cell Line Cell Line, Tumor Crystallography, X-Ray Drug Evaluation, Preclinical HSP90 Heat-Shock Proteins - antagonists & inhibitors HSP90 Heat-Shock Proteins - chemistry Humans Hydrogen Bonding Models, Molecular Molecular Structure Protein Structure, Tertiary Pyrazoles - chemistry Pyrazoles - pharmacology Structure-Activity Relationship Time Factors |
| title | Crystal structures of human HSP90alpha-complexed with dihydroxyphenylpyrazoles |
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