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PDBsum entry 2o2n
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References listed in PDB file
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Key reference
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Title
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Studies leading to potent, Dual inhibitors of bcl-2 and bcl-Xl.
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Authors
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M.Bruncko,
T.K.Oost,
B.A.Belli,
H.Ding,
M.K.Joseph,
A.Kunzer,
D.Martineau,
W.J.Mcclellan,
M.Mitten,
S.C.Ng,
P.M.Nimmer,
T.Oltersdorf,
C.M.Park,
A.M.Petros,
A.R.Shoemaker,
X.Song,
X.Wang,
M.D.Wendt,
H.Zhang,
S.W.Fesik,
S.H.Rosenberg,
S.W.Elmore.
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Ref.
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J Med Chem, 2007,
50,
641-662.
[DOI no: ]
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PubMed id
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Abstract
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Overexpression of the antiapototic proteins Bcl-2 and Bcl-xL provides a common
mechanism through which cancer cells gain a survival advantage and become
resistant to conventional chemotherapy. Inhibition of these prosurvival proteins
is an attractive strategy for cancer therapy. We recently described the
discovery of a selective Bcl-xL antagonist that potentiates the antitumor
activity of chemotherapy and radiation. Here we describe the use of
structure-guided design to exploit a deep hydrophobic binding pocket on the
surface of these proteins to develop the first dual, subnanomolar inhibitors of
Bcl-xL and Bcl-2. This study culminated in the identification of 2, which
exhibited EC50 values of 8 nM and 30 nM in Bcl-2 and Bcl-xL dependent cells,
respectively. Compound 2 demonstrated single agent efficacy against human
follicular lymphoma cell lines that overexpress Bcl-2, and efficacy in a murine
xenograft model of lymphoma when given both as a single agent and in combination
with etoposide.
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