Abstract
Information from X-ray crystal structures were used to optimize the potency of a HTS hit in a Hsp90 competitive binding assay. A class of novel and potent small molecule Hsp90 inhibitors were thereby identified. Enantio-pure compounds 31 and 33 were potent in PGA-based competitive binding assay and inhibited proliferation of various human cancer cell lines in vitro, with IC(50) values averaging 20 nM.
MeSH terms
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Amides / chemical synthesis*
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Amides / chemistry
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Amides / pharmacology*
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Amino Acids / chemistry
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Combinatorial Chemistry Techniques
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Crystallography, X-Ray
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Drug Design
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Drug Screening Assays, Antitumor
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HSP90 Heat-Shock Proteins / antagonists & inhibitors*
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Humans
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Molecular Chaperones / metabolism
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Molecular Conformation
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Molecular Structure
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Structure-Activity Relationship
Substances
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Amides
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Amino Acids
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Antineoplastic Agents
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HSP90 Heat-Shock Proteins
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Molecular Chaperones