Molecular characterization of macbecin as an Hsp90 inhibitor

Macbecin compares favorably to geldanamycin as an Hsp90 inhibitor, being more soluble, stable, more potently inhibiting ATPase activity (IC(50) = 2 mu M) and binding with higher affinity (K(d) = 0.24 mu M). Structural studies reveal significant differences in their Hsp90 binding characteristics, and macbecin-induced tumor cell growth inhibition is accompanied by characteristic degradation of Hsp90 client proteins. Macbecin significantly reduced tumor growth rates (minimum TIC: 32%) in a DU145 murine xenograft. Macbecin thus represents an attractive lead for further optimization.