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

Kosan Biosciences Incorporated, 3832 Bay Center Place, Hayward, California 94545, USA.
Journal of Medicinal Chemistry (Impact Factor: 5.45). 03/2009; 52(6):1518-21. DOI: 10.1021/jm900012a
Source: PubMed


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.

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    • "The availability of DNA sequence for numerous biosynthetic gene clusters, methods for their manipulation and advances in our understanding of biosynthetic enzymology has greatly enhanced our ability to modify the products of these pathways using genetic engineering (Walsh and Fischbach, 2010; Wilkinson and Micklefield, 2007; Wong and Khosla, 2012; Wu et al., 2012). Indeed, many clinically and commercially relevant molecules have now been modified using these techniques, providing analogs that are not generally accessible by conventional chemical techniques and which display usefully altered or improved pharmacological properties (Alexander et al., 2010; Marsden et al., 1998; Menzella et al., 2009; Sheehan et al., 2006; Zhang et al., 2008). "
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    • "Based upon the 17-AAG backbone, a nonquinone phenol derivative has been shown to have antitumor activity in mouse xenograft models and a signature HSP90 inhibitor pharmacodynamic response [Menzella et al. 2009; Zhang et al. 2008]. These compounds are currently in preclinical development. "
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