Molecular characterization of macbecin as an Hsp90 inhibitor.
Martin CJ,
Gaisser S,
Challis IR,
Carletti I,
Wilkinson B,
Gregory M,
Prodromou C,
Roe SM,
Pearl LH,
Boyd SM,
Zhang MQ.
Biotica Technology Limited, Chesterford Research Park, Essex CB10 1XL, U.K. christine.martin@biotica.com
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.
PMID: 18357975 [PubMed - indexed for MEDLINE]