Document Detail


Discovery and design of novel HSP90 inhibitors using multiple fragment-based design strategies.
MedLine Citation:
PMID:  17630989     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The molecular chaperone HSP90 has been shown to facilitate cancer cell survival by stabilizing key proteins responsible for a malignant phenotype. We report here the results of parallel fragment-based drug design approaches in the design of novel HSP90 inhibitors. Initial aminopyrimidine leads were elaborated using high-throughput organic synthesis to yield nanomolar inhibitors of the enzyme. Second site leads were also identified which bound to HSP90 in two distinct conformations, an 'open' and 'closed' form. Intriguingly, linked fragment approaches targeting both of these conformations were successful in producing novel, micromolar inhibitors. Overall, this study shows that, with only a few fragment hits, multiple lead series can be generated for HSP90 due to the inherent flexibility of the active site. Thus, ample opportunities exist to use these lead series in the development of clinically useful HSP90 inhibitors for the treatment of cancers.
Authors:
Jeffrey R Huth; Chang Park; Andrew M Petros; Aaron R Kunzer; Michael D Wendt; Xilu Wang; Christopher L Lynch; Jamey C Mack; Kerry M Swift; Russell A Judge; Jun Chen; Paul L Richardson; Sha Jin; Stephen K Tahir; Edward D Matayoshi; Sarah A Dorwin; Uri S Ladror; Jean M Severin; Karl A Walter; Diane M Bartley; Stephen W Fesik; Steven W Elmore; Philip J Hajduk
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Chemical biology & drug design     Volume:  70     ISSN:  1747-0277     ISO Abbreviation:  -     Publication Date:  2007 Jul 
Date Detail:
Created Date:  2007-07-16     Completed Date:  2008-01-14     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101262549     Medline TA:  Chem Biol Drug Des     Country:  England    
Other Details:
Languages:  eng     Pagination:  1-12     Citation Subset:  IM    
Affiliation:
Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA.
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MeSH Terms
Descriptor/Qualifier:
Aminopyridines / chemistry,  metabolism
Crystallography, X-Ray
Drug Design*
Enzyme Inhibitors* / chemical synthesis,  chemistry,  metabolism
HSP90 Heat-Shock Proteins / antagonists & inhibitors*
Humans
Ligands
Models, Molecular
Molecular Sequence Data
Molecular Structure
Nuclear Magnetic Resonance, Biomolecular
Peptide Fragments* / chemistry,  metabolism
Protein Conformation
Chemical
Reg. No./Substance:
0/Aminopyridines; 0/Enzyme Inhibitors; 0/HSP90 Heat-Shock Proteins; 0/Ligands; 0/Peptide Fragments

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