Abstract
A biosynthetic medicinal chemistry approach was applied to the optimization of the natural product Hsp90 inhibitor macbecin. By genetic engineering, mutants have been created to produce novel macbecin analogues including a nonquinone compound (5) that has significantly improved binding affinity to Hsp90 (Kd 3 nM vs 240 nM for macbecin) and reduced toxicity (MTD > or = 250 mg/kg). Structural flexibility may contribute to the preorganization of 5 to exist in solution in the Hsp90-bound conformation.
MeSH terms
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Benzoquinones / chemistry
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Benzoquinones / metabolism
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Benzoquinones / pharmacology*
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Biological Products / chemistry
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Biological Products / metabolism
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Biological Products / pharmacology*
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Genetic Engineering*
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HSP90 Heat-Shock Proteins / antagonists & inhibitors*
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HSP90 Heat-Shock Proteins / metabolism
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Lactams, Macrocyclic / chemistry
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Lactams, Macrocyclic / metabolism
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Lactams, Macrocyclic / pharmacology*
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Molecular Sequence Data
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Molecular Structure
Substances
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Benzoquinones
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Biological Products
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HSP90 Heat-Shock Proteins
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Lactams, Macrocyclic
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macbecin I