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 (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.
Martin
Christine J
CJ
Biotica Technology Limited, Chesterford Research Park, Essex CB10 1XL, U.K. christine.martin@biotica.com
Gaisser
Sabine
S
Challis
Iain R
IR
Carletti
Isabelle
I
Wilkinson
Barrie
B
Gregory
Matthew
M
Prodromou
Chrisostomos
C
Roe
S Mark
SM
Pearl
Laurence H
LH
Boyd
Susan M
SM
Zhang
Ming-Qiang
MQ
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D016227:Benzoquinones / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D006801:Humans; D047029:Lactams, Macrocyclic / Q000737:chemistry* / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D013816:Thermodynamics; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C025514:macbecin I