Preclinical study demonstrates potent Hsp90 inhibition and reduced toxicity by a novel macbecin analogue, suggesting a viable route for safer drug development.
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.
No takes yet. Share an insight, caveat, or question.
Zhang et al. (2008) studied this question.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: