Optimizing Natural Products by Biosynthetic Engineering: Discovery of Nonquinone Hsp90 Inhibitors
journal contributionposted on 25.09.2008, 00:00 by 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, Christine J. Martin
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 ≥ 250 mg/kg). Structural flexibility may contribute to the preorganization of 5 to exist in solution in the Hsp90-bound conformation.