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Cancer Chemistry

Precursor-directed biosynthesis of macbecin analogues: generation of non-quinone containing Hsp90 inhibitors and pre-clinical evaluation

Christine Martin, Bill Vousden, Sabine Gaisser, Mohammed Nur-E-Alam, Nigel Coates, Christoph Beckman, Barrie Wilkinson, Matthew Gregory, Chrisostomos Prodromou, Mark Roe, Laurence Pearl, Susan Boyd, Thomas Greiner, Niko Bausch and Ming-Qiang Zhang
Christine Martin
Biotica Technology Ltd., Little Chesterford, United Kingdom, Institute of Cancer Research, London, United Kingdom, CompChem Solutions, Cambridge, United Kingdom, Oncotest GmbH, Freiburg, Germany
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Bill Vousden
Biotica Technology Ltd., Little Chesterford, United Kingdom, Institute of Cancer Research, London, United Kingdom, CompChem Solutions, Cambridge, United Kingdom, Oncotest GmbH, Freiburg, Germany
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Sabine Gaisser
Biotica Technology Ltd., Little Chesterford, United Kingdom, Institute of Cancer Research, London, United Kingdom, CompChem Solutions, Cambridge, United Kingdom, Oncotest GmbH, Freiburg, Germany
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Mohammed Nur-E-Alam
Biotica Technology Ltd., Little Chesterford, United Kingdom, Institute of Cancer Research, London, United Kingdom, CompChem Solutions, Cambridge, United Kingdom, Oncotest GmbH, Freiburg, Germany
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Nigel Coates
Biotica Technology Ltd., Little Chesterford, United Kingdom, Institute of Cancer Research, London, United Kingdom, CompChem Solutions, Cambridge, United Kingdom, Oncotest GmbH, Freiburg, Germany
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Christoph Beckman
Biotica Technology Ltd., Little Chesterford, United Kingdom, Institute of Cancer Research, London, United Kingdom, CompChem Solutions, Cambridge, United Kingdom, Oncotest GmbH, Freiburg, Germany
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Barrie Wilkinson
Biotica Technology Ltd., Little Chesterford, United Kingdom, Institute of Cancer Research, London, United Kingdom, CompChem Solutions, Cambridge, United Kingdom, Oncotest GmbH, Freiburg, Germany
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Matthew Gregory
Biotica Technology Ltd., Little Chesterford, United Kingdom, Institute of Cancer Research, London, United Kingdom, CompChem Solutions, Cambridge, United Kingdom, Oncotest GmbH, Freiburg, Germany
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Chrisostomos Prodromou
Biotica Technology Ltd., Little Chesterford, United Kingdom, Institute of Cancer Research, London, United Kingdom, CompChem Solutions, Cambridge, United Kingdom, Oncotest GmbH, Freiburg, Germany
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Mark Roe
Biotica Technology Ltd., Little Chesterford, United Kingdom, Institute of Cancer Research, London, United Kingdom, CompChem Solutions, Cambridge, United Kingdom, Oncotest GmbH, Freiburg, Germany
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Laurence Pearl
Biotica Technology Ltd., Little Chesterford, United Kingdom, Institute of Cancer Research, London, United Kingdom, CompChem Solutions, Cambridge, United Kingdom, Oncotest GmbH, Freiburg, Germany
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Susan Boyd
Biotica Technology Ltd., Little Chesterford, United Kingdom, Institute of Cancer Research, London, United Kingdom, CompChem Solutions, Cambridge, United Kingdom, Oncotest GmbH, Freiburg, Germany
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Thomas Greiner
Biotica Technology Ltd., Little Chesterford, United Kingdom, Institute of Cancer Research, London, United Kingdom, CompChem Solutions, Cambridge, United Kingdom, Oncotest GmbH, Freiburg, Germany
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Niko Bausch
Biotica Technology Ltd., Little Chesterford, United Kingdom, Institute of Cancer Research, London, United Kingdom, CompChem Solutions, Cambridge, United Kingdom, Oncotest GmbH, Freiburg, Germany
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Ming-Qiang Zhang
Biotica Technology Ltd., Little Chesterford, United Kingdom, Institute of Cancer Research, London, United Kingdom, CompChem Solutions, Cambridge, United Kingdom, Oncotest GmbH, Freiburg, Germany
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DOI:  Published May 2008
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AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

Abstract

4157

Inhibition of Hsp90 results in the simultaneous destabilisation and degradation of multiple oncogenic client proteins leading to cell growth inhibition and apoptosis. Thus, Hsp90 is a major therapeutic target for anticancer drug development.
Existing clinical Hsp90 inhibitors of the geldanamycin-class e.g. 17-AAG, 17-DMAG and IPI-504 all contain a common ‘toxicophore’ - the quinone moiety that undergoes redox cycling in vivo which contributes to off-target toxicity and undesired side-effects. Their antitumor activities are also partially related to this quinone redox cycling and therefore dependent on the expression of the NAD(P)H:quinone oxidoreductase (NQO1).
We have previously reported the characterisation of macbecin I as an Hsp90 inhibitor and proposed it as an alternative lead to geldanamycin. Through genetic engineering of the macbecin biosynthetic pathway we prepared an analogue, BHI-001 lacking the undesired quinone moiety and with further structural modifications in the ansa ring which allow it to adopt the active conformation for binding to Hsp90 more readily. This compound is a very potent inhibitor of Hsp90 with a binding affinity (Kd) of 3 nM.
We now report a series of non-quinone containing ansamycin analogues of BHI-001 as potent Hsp90 inhibitors. Precursor-directed biosynthesis of these BHI-001 analogues was achieved by feeding substituted benzoic acids to the mutant strain of Actinosynemma pretiosum. We shall present preclinical data on this series of novel polyketides including X-ray crystallography data for the rationalization of the structure-activity-relationship observed. Furthermore, semi-synthetic derivatization of BHI-001 generated novel derivatives with markedly increased water solubility and tolerability. The utilization of genetic engineering, precursor-directed biosynthesis and semi-synthesis provides excellent access to novel structural space, demonstrating the utilities of biosynthetic medicinal chemistry in optimization of natural product leads.

Footnotes

  • 99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

  • American Association for Cancer Research
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Cancer Research: 68 (9 Supplement)
May 2008
Volume 68, Issue 9 Supplement
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Precursor-directed biosynthesis of macbecin analogues: generation of non-quinone containing Hsp90 inhibitors and pre-clinical evaluation
Christine Martin, Bill Vousden, Sabine Gaisser, Mohammed Nur-E-Alam, Nigel Coates, Christoph Beckman, Barrie Wilkinson, Matthew Gregory, Chrisostomos Prodromou, Mark Roe, Laurence Pearl, Susan Boyd, Thomas Greiner, Niko Bausch and Ming-Qiang Zhang
Cancer Res May 1 2008 (68) (9 Supplement) 4157;

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Precursor-directed biosynthesis of macbecin analogues: generation of non-quinone containing Hsp90 inhibitors and pre-clinical evaluation
Christine Martin, Bill Vousden, Sabine Gaisser, Mohammed Nur-E-Alam, Nigel Coates, Christoph Beckman, Barrie Wilkinson, Matthew Gregory, Chrisostomos Prodromou, Mark Roe, Laurence Pearl, Susan Boyd, Thomas Greiner, Niko Bausch and Ming-Qiang Zhang
Cancer Res May 1 2008 (68) (9 Supplement) 4157;
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