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.
"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). "
[Show abstract][Hide abstract] ABSTRACT: The rapK gene required for biosynthesis of the DHCHC starter acid that initiates rapamycin biosynthesis was deleted from strain BIOT-3410, a derivative of S. rapamycinicus which had been subjected to classical strain and process development and capable of robust rapamycin production at titres up to 250mg/L. The resulting strain BIOT-4010 could no longer produce rapamycin, but when supplied exogenously with DHCHC produced rapamycin at titres equivalent to its parent strain. This strain enabled mutasynthetic access to new rapalogs that could not readily be isolated from lower titre strains when fed DHCHC analogs. Mutasynthesis of some rapalogs resulted predominantly in compounds lacking late post polyketide synthase biosynthetic modifications. To enhance the relative production of fully elaborated rapalogs, genes encoding late-acting biosynthetic pathway enzymes which failed to act efficiently on the novel compounds were expressed ectopically to give strain BIOT-4110. Strains BIOT-4010 & BIOT-4110 represent valuable tools for natural product lead optimization using biosynthetic medicinal chemistry and for the production of rapalogs for pre-clinical and early stage clinical trials.
"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. "
[Show abstract][Hide abstract] ABSTRACT: Heat shock protein 90 (HSP90) is a molecular chaperone protein essential for cellular survival. Functionally, HSPs promote proper protein folding, prevent misfolding, and restore three-dimensional protein structure which is critical following toxic cellular stresses. Recently, targeting HSP90 pharmacologically has gained traction in cancer therapy. Oncogenic cells depend on their ability to withstand endogenous (anoxia, nutrient deprivation, pH changes, and deranged signaling pathways) and exogenous (chemotherapy and radiation therapy) stressors for survival. Pharmacological inhibition of HSP90 destabilizes proteins and leads to degradation through the proteasome. This article will review the utility of HSP90 inhibition, as well as the current adoption in clinical trials and practice.
rapeutic Advances in Medical Oncology, The 07/2012; 4(4):211-8. DOI:10.1177/1758834012445574 · 2.83 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In the past four years, the ATP-dependent heat-shock protein 90 has remained the focus of much interest. Phase I and phase II anticancer clinical trials with first-generation inhibitors, although sometimes disappointing, have yet to report a forbidding side-effect inherent to the inhibition of this chaperone, which has a very complex and widespread role in cell biochemistry. Research in the field has started to unravel an elaborate regulation picture leading to the proper folding of many proteins. On the medicinal chemistry side, a second wave of inhibitors has been reported. This review attempts to describe all the ATPase inhibitors of HSP90 reported since our last survey.
Drug discovery today 03/2010; 15(9-10):342-53. DOI:10.1016/j.drudis.2010.03.002 · 6.69 Impact Factor
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