3-(5-chloro-2,4-dihydroxyphenyl)-Pyrazole-4-carboxamides as inhibitors of the Hsp90 molecular chaperone

Structure-based drug design using information from X-ray structures of ligands bound to the molecular chaperone Hsp90 has been used to assist in the design of 3-(5-chloro-2,4-dihydroxyphenyl)-pyrazole-4-carboxamides, several of which can make a hydrogen bond to Phe138 of the protein, affording incre...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2005-12, Vol.15 (23), p.5197-5201
Main Authors: Brough, Paul A., Barril, Xavier, Beswick, Mandy, Dymock, Brian W., Drysdale, Martin J., Wright, Lisa, Grant, Kate, Massey, Andrew, Surgenor, Allan, Workman, Paul
Format: Article
Language:English
Subjects:
Amides - chemistry
Amides - pharmacology
Antineoplastic agents
Biological and medical sciences
Cancer
Crystallography, X-Ray
Drug Design
General aspects
Hsp90
HSP90 Heat-Shock Proteins - antagonists & inhibitors
Humans
Medical sciences
Molecular Structure
Oxamic Acid - chemistry
Pharmacology. Drug treatments
Pyrazole
Pyrazoles - chemistry
Pyrazoles - pharmacology
Structure-based drug design
X-ray crystallography
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Summary:Structure-based drug design using information from X-ray structures of ligands bound to the molecular chaperone Hsp90 has been used to assist in the design of 3-(5-chloro-2,4-dihydroxyphenyl)-pyrazole-4-carboxamides, several of which can make a hydrogen bond to Phe138 of the protein, affording increased binding potency. Information from X-ray crystal structures of Hsp90 inhibitors bound to the human Hsp90 molecular chaperone was used to assist in the design of 3-(5-chloro-2,4-dihydroxyphenyl)-pyrazole-4-carboxamides as novel inhibitors of Hsp90. Accessing an extra interaction with the protein via Phe138 gave a significant increase in binding potency compared to similar analogues that do not make this interaction.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2005.08.091