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Novel, potent small-molecule inhibitors of the molecular chaperone Hsp90 discovered through structure-based design

Posted June 8th, 2010 by pschmidtke
TitleNovel, potent small-molecule inhibitors of the molecular chaperone Hsp90 discovered through structure-based design
Publication TypeJournal Article
Year of Publication2005
AuthorsDymock, BW, Barril X, Brough PA, Cansfield JE, Massey A, McDonald E, Hubbard RE, Surgenor A, Roughley SD, Webb P, Workman P, Wright L, Drysdale MJ
JournalJournal of medicinal chemistry
Volume48
Issue13
Pagination4212 - 4215
Date Published2005/06/30/
KeywordsAdenosine Triphosphate/metabolism; Amides/chemical synthesis/chemistry/pharmacology; Amines/chemical synthesis/chemistry/pharmacology; Binding Sites; Drug Design; Glycine; HSP90 Heat-Shock Proteins/antagonists & inhibitors/chemistry; Humans; Models, Molecular; Molecular Structure; Protein Conformation; Structure-Activity Relationship
AbstractThe crystal structure of a previously reported screening hit 1 (CCT018159) bound to the N terminal domain of molecular chaperone Hsp90 has been used to design 5-amide analogues. These exhibit enhanced potency against the target in binding and functional assays with accompanying appropriate cellular pharmacodynamic changes. Compound 11 (VER-49009) compares favorably with the clinically evaluated 17-AAG.