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

Brian W Dymock; Xavier Barril; Paul A Brough; Julie E Cansfield; Andrew Massey; Edward McDonald; Roderick E Hubbard; Allan Surgenor; Stephen D Roughley; Paul Webb; Paul Workman; Lisa Wright; Martin J Drysdale

doi:10.1021/jm050355z

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

J Med Chem. 2005 Jun 30;48(13):4212-5. doi: 10.1021/jm050355z.

Authors

Brian W Dymock¹, Xavier Barril, Paul A Brough, Julie E Cansfield, Andrew Massey, Edward McDonald, Roderick E Hubbard, Allan Surgenor, Stephen D Roughley, Paul Webb, Paul Workman, Lisa Wright, Martin J Drysdale

Affiliation

¹ Vernalis Ltd., Granta Park, Great Abington, Cambridge, UK.

PMID: 15974572
DOI: 10.1021/jm050355z

Abstract

The 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.

MeSH terms

Adenosine Triphosphate / metabolism
Amides / chemical synthesis
Amides / chemistry
Amides / pharmacology
Amines / chemical synthesis
Amines / chemistry
Amines / pharmacology
Binding Sites
Drug Design
Glycine
HSP90 Heat-Shock Proteins / antagonists & inhibitors*
HSP90 Heat-Shock Proteins / chemistry
Humans
Models, Molecular
Molecular Structure
Protein Conformation
Structure-Activity Relationship

Substances

Amides
Amines
HSP90 Heat-Shock Proteins
Adenosine Triphosphate
Glycine