Abstract
Heat shock protein 90 (Hsp90) is a molecular chaperone that is responsible for activating many signaling proteins and is a promising target in tumor biology. We have identified small-molecule benzisoxazole derivatives as Hsp90 inhibitors. Crystallographic studies show that these compounds bind in the ATP binding pocket interacting with the Asp93. Structure based optimization led to the identification of potent analogues, such as 13, with good biochemical profiles.
MeSH terms
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Adenosine Triphosphate / metabolism
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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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Binding Sites
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Cell Proliferation / drug effects
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Crystallography, X-Ray
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Drug Screening Assays, Antitumor
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HSP90 Heat-Shock Proteins / antagonists & inhibitors*
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HSP90 Heat-Shock Proteins / metabolism
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Humans
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Isoxazoles / chemical synthesis*
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Isoxazoles / chemistry
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Isoxazoles / pharmacology
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K562 Cells
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Models, Molecular
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Protein Conformation
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Structure-Activity Relationship
Substances
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Antineoplastic Agents
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HSP90 Heat-Shock Proteins
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Isoxazoles
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Adenosine Triphosphate