Abstract
An extension of our previously reported series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. Addition of a second methyl group to the tether provided analogs that show increased potency in binding as well as cell-proliferation assays and, more importantly, are stable toward microsomes. We wish to disclose the discovery of a macrocycle which showed impressive biomarker activity 24-h post dosing and which demonstrated prolonged exposure in tumors. When studied in a lung cancer xenograft model, the compound demonstrated significant tumor size reduction.
Copyright © 2011 Elsevier Ltd. All rights reserved.
MeSH terms
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Administration, Oral
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Animals
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Antineoplastic Agents / chemistry*
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / therapeutic use
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Benzamides / chemistry*
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Benzamides / pharmacokinetics
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Benzamides / therapeutic use
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Binding Sites
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Biomarkers / metabolism
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Drug Evaluation, Preclinical
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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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Lung Neoplasms / drug therapy*
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Macrocyclic Compounds / chemistry*
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Mice
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Mice, Nude
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Microsomes, Liver / metabolism
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Protein Structure, Tertiary
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Rats
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Transplantation, Heterologous
Substances
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Antineoplastic Agents
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Benzamides
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Biomarkers
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HSP90 Heat-Shock Proteins
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Macrocyclic Compounds
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benzamide