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Letter

Optimizing Natural Products by Biosynthetic Engineering: Discovery of Nonquinone Hsp90 Inhibitors^†

Supporting Info

Ming-Qiang Zhang^‡, Sabine Gaisser^‡, Mohammad Nur-E-Alam^‡, Lesley S. Sheehan^‡, William A. Vousden^‡, Nikolaos Gaitatzis^‡, Gerrard Peck^‡, Nigel J. Coates^‡, Steven J. Moss^‡, Markus Radzom^‡, Teresa A. Foster^‡, Rose M. Sheridan^‡, Matthew A. Gregory^‡, S. Mark Roe^§, Chrisostomos Prodromou^§, Laurence Pearl^§, Susan M. Boyd, Barrie Wilkinson^‡ and Christine J. Martin*^‡

Biotica Technology Limited, Chesterford Research Park, Nr. Saffron Walden, Essex CB10 1XL, United Kingdom, Section of Structural Biology, Chester Beatty Laboratories, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, United Kingdom, CompChem Solutions, St. John’s Innovation Centre, Cowley Road, Cambridge CB4 0WS, United Kingdom

J. Med. Chem., 2008, 51 (18), pp 5494–5497

DOI: 10.1021/jm8006068

Publication Date (Web): August 23, 2008

†

PDB code of crystal structure of 5 bound to Hsp90: 2VW5. Accession number for macbecin biosynthesis cluster: EU827593.

‡

Biotica Technology Limited.

Institute of Cancer Research.

CompChem Solutions.

* To whom correspondence should be addressed. Phone: +44 1799 532927. Fax: +44 1799 532921. E-mail: christine.martin@biotica.com.

Abstract

A biosynthetic medicinal chemistry approach was applied to the optimization of the natural product Hsp90 inhibitor macbecin. By genetic engineering, mutants have been created to produce novel macbecin analogues including a nonquinone compound (5) that has significantly improved binding affinity to Hsp90 (K_d 3 nM vs 240 nM for macbecin) and reduced toxicity (MTD ≥ 250 mg/kg). Structural flexibility may contribute to the preorganization of 5 to exist in solution in the Hsp90-bound conformation.

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History

Published In Issue September 25, 2008
Article ASAPAugust 23, 2008
Received: May 21, 2008

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Letter

Optimizing Natural Products by Biosynthetic Engineering: Discovery of Nonquinone Hsp90 Inhibitors^†