ORGANIC
LETTERS
2005
Vol. 7, No. 11
2157-2160
Radester, a Novel Inhibitor of the Hsp90
Protein Folding Machinery
Gang Shen and Brian S. J. Blagg*
Department of Medicinal Chemistry and The Center for Protein Structure and
Function, The UniVersity of Kansas, 1251 Wescoe Hall DriVe, Malott 4070,
Lawrence, Kansas 66045-7562
Received March 16, 2005
ABSTRACT
The antitumor antibiotics radicicol and geldanamycin are potent inhibitors of the Hsp90 protein folding machinery. Radester is a hybrid
composed of radicicol’s resorcinol ring and geldanamycin’s quinone through an isopropyl ester. Radester was prepared, and the cytotoxicity
of it and the corresponding hydroquinone were determined in MCF-7 breast cancer cells to be 13.9 and 7.1
µM, respectively. Protein degradation
assays were performed on Hsp90-dependent client proteins, Her-2 and Raf, to correlate Hsp90 inhibition to cytotoxicity.
Hsp90 (90 kDa heat shock protein) is a molecular chaperone
responsible for the conformational maturation of numerous
oncogenic proteins.1 Inhibition of Hsp90 turns the protein
folding machinery into a catalyst for protein degradation.
Recent studies have demonstrated that Hsp90 multiprotein
complexes from tumor cells have higher affinity for ligands
than Hsp90 in normal cells, because malignant cells are
highly dependent upon the Hsp90 protein folding machinery
for the maturation of mutated and over expressed client
proteins that are vital to cell proliferation and growth.2 In
fact, proteins represented in all six hallmarks of cancer are
dependent on the Hsp90 maturation process. Consequently,
Hsp90 has emerged as a promising biological target for the
treatment of cancer, because inhibition of Hsp90 results in
a combinatorial blockade of multiple signaling cascades that
are essential to tumor cell survival.3
and the other in the C-terminal region.4 The energy derived
from ATP hydrolysis is used to fold the nascent polypeptide
into a biologically active protein. Disruption of Hsp90’s
ATPase activity results in the destabilization of multiprotein
complexes and subsequent degradation of the client via the
ubiquitin-proteasome pathway.5
Known inhibitors of Hsp90 manifest their activity by
binding to the N-terminal ATP binding pocket and preventing
Hsp90-catalyzed hydrolysis of ATP. Such inhibitors include
the antitumor antibiotics geldanamycin (GDA), a 17-allyl-
amino derivative of GDA (17-AAG), radicicol (RDC), and
the synthetic ATP analogue PU3 (Figure 1).6 The IC50’s as
determined in MCF-7 cells are 49 nM, 23 nM,7 and 50 µM
for GDA, RDC, and PU3, respectively.
(4) Marcu, M. G.; Chadli, A.; Bouhouche, I.; Catelli, N.; Neckers, L.
M. J. Biol. Chem. 2000, 276, 37181.
(5) Binder, R. J.; Blachere, N. E.; Srivastava, P. K. J. Biol. Chem. 2001,
276, 17163.
Hsp90 is an ATP-dependent protein with two nucleotide-
binding domains, one of which is located in the N-terminus
(6) Chiosis, G.; Vilenchik, M.; Kim, J.; Solit, D. Drug DiscoVery Today
(1) Zhang, H.; Burrows, F. J. Mol. Med. 2004, 82, 488.
(2) Kamal, A.; Thao, L.; Sensintaffar, J.; Zhang, L.; Boehm, M. F.; Fritz,
L. C.; Burrows, F. J. Nature 2003, 425, 407.
2004, 9, 881.
(7) Yamamoto, K.; Garbaccio, R. M.; Stachel, S. J.; Solit, D. B.; Chiosis,
G.; Rosen, N.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2003, 42,
1280.
(3) Neckers, L.; Lee, Y.-S. Nature 2003, 425, 357.
10.1021/ol050580a CCC: $30.25
© 2005 American Chemical Society
Published on Web 05/03/2005