title: 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.
authors.affiliation: Genomics Institute of the Novartis Research Foundation (GNF), 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kreusch
authors.forename: Shulin
authors.initials: S
authors.lastname: Han
authors.forename: Achim
authors.initials: A
authors.lastname: Brinker
authors.forename: Vicki
authors.initials: V
authors.lastname: Zhou
authors.forename: Ha-soon
authors.initials: HS
authors.lastname: Choi
authors.forename: Yun
authors.initials: Y
authors.lastname: He
authors.forename: Scott A
authors.initials: SA
authors.lastname: Lesley
authors.forename: Jeremy
authors.initials: J
authors.lastname: Caldwell
authors.forename: Xiang-ju
authors.initials: XJ
authors.lastname: Gu
mesh_terms: D002460:Cell Line; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D015394:Molecular Structure; D017434:Protein Structure, Tertiary; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: C501630:G3129; C501629:G3130; D018841:HSP90 Heat-Shock Proteins; D011720:Pyrazoles