Potent Non-Benzoquinone Ansamycin Heat Shock Protein 90 Inhibitors from Genetic Engineering of Streptomyces hygroscopicus

Inhibition of the protein chaperone Hsp90 is a promising new approach to cancer therapy. We describe the preparation of potent non-benzoquinone ansamycins. One of these analogues, generated by feeding 3-amino-5-chlorobenzoic acid to a genetically engineered strain of Streptomyces hygroscopicus, show...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2009-03, Vol.52 (6), p.1518-1521
Main Authors: Menzella, Hugo G, Tran, Thomas-Toan, Carney, John R, Lau-Wee, Janice, Galazzo, Jorge, Reeves, Christopher D, Carreras, Christopher, Mukadam, Sophie, Eng, Sara, Zhong, Ziyang, Timmermans, Pieter B. M. W. M, Murli, Sumati, Ashley, Gary W
Format: Article
Language:English
Subjects:
Antineoplastic agents
Antineoplastic drugs. Cytokines
Biological and medical sciences
Biotechnology
Calorimetry
Cell Division - drug effects
Cell Line, Tumor
Fundamental and applied biological sciences. Psychology
General aspects
Genetic Engineering
Health. Pharmaceutical industry
HSP90 Heat-Shock Proteins - antagonists & inhibitors
Humans
Industrial applications and implications. Economical aspects
Medical sciences
Pharmacology. Drug treatments
Production of active biomolecules
Rifabutin - pharmacology
Streptomyces - genetics
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Summary:Inhibition of the protein chaperone Hsp90 is a promising new approach to cancer therapy. We describe the preparation of potent non-benzoquinone ansamycins. One of these analogues, generated by feeding 3-amino-5-chlorobenzoic acid to a genetically engineered strain of Streptomyces hygroscopicus, shows high accumulation and long residence time in tumor tissue, is well-tolerated upon intravenous dosing, and is highly efficacious in the COLO205 mouse tumor xenograft model.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm900012a