Optimizing Natural Products by Biosynthetic Engineering: Discovery of Nonquinone Hsp90 Inhibitors
- 23 August 2008
- journal article
- letter
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 51 (18) , 5494-5497
- https://doi.org/10.1021/jm8006068
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 (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.Keywords
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