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 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.
Kreusch
Andreas
A
Genomics Institute of the Novartis Research Foundation (GNF), 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA.
Han
Shulin
S
Brinker
Achim
A
Zhou
Vicki
V
Choi
Ha-soon
HS
He
Yun
Y
Lesley
Scott A
SA
Caldwell
Jeremy
J
Gu
Xiang-ju
XJ
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
C501630:G3129; C501629:G3130; D018841:HSP90 Heat-Shock Proteins; D011720:Pyrazoles