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

2008; American Chemical Society; Volume: 51; Issue: 18 Linguagem: Inglês

10.1021/jm8006068

1520-4804

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 Sheridan, Matthew A. Gregory, S. Mark Roe, Chrisostomos Prodromou, Laurence H. Pearl, Susan M. Boyd, Barrie Wilkinson, Christine Martin,

Computational Drug Discovery Methods

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 (Kd 3 nM vs 240 nM for macbecin) and reduced toxicity (MTD > or = 250 mg/kg). Structural flexibility may contribute to the preorganization of 5 to exist in solution in the Hsp90-bound conformation.