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PDBsum entry 2wi3
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References listed in PDB file
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Key reference
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Title
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Combining hit identification strategies: fragment-Based and in silico approaches to orally active 2-Aminothieno[2,3-D]pyrimidine inhibitors of the hsp90 molecular chaperone.
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Authors
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P.A.Brough,
X.Barril,
J.Borgognoni,
P.Chene,
N.G.Davies,
B.Davis,
M.J.Drysdale,
B.Dymock,
S.A.Eccles,
C.Garcia-Echeverria,
C.Fromont,
A.Hayes,
R.E.Hubbard,
A.M.Jordan,
M.R.Jensen,
A.Massey,
A.Merrett,
A.Padfield,
R.Parsons,
T.Radimerski,
F.I.Raynaud,
A.Robertson,
S.D.Roughley,
J.Schoepfer,
H.Simmonite,
S.Y.Sharp,
A.Surgenor,
M.Valenti,
S.Walls,
P.Webb,
M.Wood,
P.Workman,
L.Wright.
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Ref.
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J Med Chem, 2009,
52,
4794-4809.
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PubMed id
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Abstract
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Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as
potential molecular therapeutic agents for the treatment of cancer. Here we
describe novel 2-aminothieno[2,3-d]pyrimidine ATP competitive Hsp90 inhibitors,
which were designed by combining structural elements of distinct low affinity
hits generated from fragment-based and in silico screening exercises in concert
with structural information from X-ray protein crystallography. Examples from
this series have high affinity (IC50 = 50-100 nM) for Hsp90 as measured in a
fluorescence polarization (FP) competitive binding assay and are active in human
cancer cell lines where they inhibit cell proliferation and exhibit a
characteristic profile of depletion of oncogenic proteins and concomitant
elevation of Hsp72. Several examples (34a, 34d and 34i) caused tumor growth
regression at well tolerated doses when administered orally in a human BT474
human breast cancer xenograft model.
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