Abstract
Macbecin compares favorably to geldanamycin as an Hsp90 inhibitor, being more soluble, stable, more potently inhibiting ATPase activity (IC50 = 2 microM) and binding with higher affinity (Kd = 0.24 microM). Structural studies reveal significant differences in their Hsp90 binding characteristics, and macbecin-induced tumor cell growth inhibition is accompanied by characteristic degradation of Hsp90 client proteins. Macbecin significantly reduced tumor growth rates (minimum T/C: 32%) in a DU145 murine xenograft. Macbecin thus represents an attractive lead for further optimization.
MeSH terms
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Animals
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Antineoplastic Agents / chemistry*
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Antineoplastic Agents / pharmacology
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Benzoquinones / chemistry*
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Benzoquinones / pharmacology
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Cell Line, Tumor
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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 / biosynthesis
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Humans
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Lactams, Macrocyclic / chemistry*
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Lactams, Macrocyclic / pharmacology
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Mice
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Models, Molecular
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Molecular Structure
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Protein Binding
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Thermodynamics
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Transplantation, Heterologous
Substances
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Antineoplastic Agents
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Benzoquinones
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HSP90 Heat-Shock Proteins
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Lactams, Macrocyclic
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macbecin I