Molecular characterization of macbecin as an Hsp90 inhibitor

Christine J Martin, Sabine Gaisser, Iain R Challis, Isabelle Carletti, Barrie Wilkinson, Matthew Gregory, Chrisostomos Prodromou, S Mark Roe, Laurence H Pearl, Susan M Boyd, Ming-Qiang Zhang
Journal of Medicinal Chemistry 2008 May 8, 51 (9): 2853-7
Macbecin compares favorably to geldanamycin as an Hsp90 inhibitor, being more soluble, stable, more potently inhibiting ATPase activity (IC50 = 2 microM) and binding with higher affinity (Kd = 0.24 microM). 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 T/C: 32%) in a DU145 murine xenograft. Macbecin thus represents an attractive lead for further optimization.

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