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PDBsum entry 2iwu
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References listed in PDB file
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Key reference
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Title
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Inhibition of hsp90 with synthetic macrolactones: synthesis and structural and biological evaluation of ring and conformational analogs of radicicol.
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Authors
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N.Proisy,
S.Y.Sharp,
K.Boxall,
S.Connelly,
S.M.Roe,
C.Prodromou,
A.M.Slawin,
L.H.Pearl,
P.Workman,
C.J.Moody.
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Ref.
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Chem Biol, 2006,
13,
1203-1215.
[DOI no: ]
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PubMed id
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Abstract
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A series of benzo-macrolactones of varying ring size and conformation has been
prepared by chemical synthesis and evaluated by structural and biological
techniques. Thus, 12- to 16-membered lactones were obtained by concise routes,
involving ring-closing metathesis as a key step. In enzyme assays, the 13-, 15-,
and 16-membered analogs are good inhibitors, suggesting that they can adopt the
required conformation to fit in the ATP-binding site. This was confirmed by
cocrystallization of 13-, 14-, and 15-membered lactones with the N-terminal
domain of yeast Hsp90, showing that they bind similarly to the
"natural" 14-membered radicicol. The most active compounds in the
ATPase assays also showed the greatest growth-inhibitory potency in HCT116 human
colon cancer cells and the established molecular signature of Hsp90 inhibition,
i.e., depletion of client proteins with upregulation of Hsp70.
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Figure 2.
Figure 2. Binding Interactions of Macrolactone Inhibitors
with Yeast Hsp90
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Figure 5.
Figure 5. Molecular Modeling
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The above figures are
reprinted
by permission from Cell Press:
Chem Biol
(2006,
13,
1203-1215)
copyright 2006.
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