Optimizing natural products by biosynthetic engineering: Discovery of nonquinone Hsp90 inhibitors

A biosynthetic medicinal chemistry approach was applied to the optimization of the natural product Hsp90 inhibitor macbecin. By genetic engineering, mutant, 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.