Abstract
17-Allylamino-17-demethoxygeldanamycin (17-AAG)1 is a semisynthetic inhibitor of the 90 kDa heat shock protein (Hsp90) currently in clinical trials for the treatment of cancer. However, 17-AAG faces challenging formulation issues due to its poor solubility. Here we report the synthesis and evaluation of a highly soluble hydroquinone hydrochloride derivative of 17-AAG, 1a (IPI-504), and several of the physiological metabolites. These compounds show comparable binding affinity to human Hsp90 and its endoplasmic reticulum (ER) homologue, the 94 kDa glucose regulated protein (Grp94). Furthermore, the compounds inhibit the growth of the human cancer cell lines SKBR3 and SKOV3, which overexpress Hsp90 client protein Her2, and cause down-regulation of Her2 as well as induction of Hsp70 consistent with Hsp90 inhibition. There is a clear correlation between the measured binding affinity of the compounds and their cellular activities. Upon the basis of its potent activity against Hsp90 and a significant improvement in solubility, 1a is currently under evaluation in Phase I clinical trials for cancer.
MeSH terms
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Animals
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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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Benzoquinones / chemical synthesis*
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Benzoquinones / chemistry
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Benzoquinones / pharmacology
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Binding, Competitive
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Cell Line, Tumor
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Dogs
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Drug Screening Assays, Antitumor
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Fluorescence Polarization
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HSP70 Heat-Shock Proteins / biosynthesis
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HSP70 Heat-Shock Proteins / chemistry
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HSP90 Heat-Shock Proteins / antagonists & inhibitors*
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HSP90 Heat-Shock Proteins / chemistry
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Humans
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Hydroquinones / chemical synthesis*
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Hydroquinones / chemistry
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Hydroquinones / pharmacology
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Lactams, Macrocyclic / chemical synthesis*
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Lactams, Macrocyclic / chemistry
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Lactams, Macrocyclic / pharmacology
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Membrane Proteins / chemistry
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Models, Molecular
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Protein Isoforms / chemistry
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Receptor, ErbB-2 / antagonists & inhibitors
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Receptor, ErbB-2 / biosynthesis
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Rifabutin / analogs & derivatives*
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Rifabutin / chemical synthesis
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Rifabutin / chemistry
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Rifabutin / pharmacology
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Solubility
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Structure-Activity Relationship
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Water
Substances
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Antineoplastic Agents
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Benzoquinones
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HSP70 Heat-Shock Proteins
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HSP90 Heat-Shock Proteins
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Hydroquinones
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Lactams, Macrocyclic
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Membrane Proteins
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Protein Isoforms
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glucose-regulated proteins
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Water
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Rifabutin
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tanespimycin
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Receptor, ErbB-2