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PDBsum entry 4zbi
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Apoptosis/apoptosis inhibitor
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PDB id
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4zbi
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References listed in PDB file
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Key reference
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Title
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Discovery of tricyclic indoles that potently inhibit mcl-1 using fragment-Based methods and structure-Based design.
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Authors
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J.P.Burke,
Z.Bian,
S.Shaw,
B.Zhao,
C.M.Goodwin,
J.Belmar,
C.F.Browning,
D.Vigil,
A.Friberg,
D.V.Camper,
O.W.Rossanese,
T.Lee,
E.T.Olejniczak,
S.W.Fesik.
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Ref.
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J Med Chem, 2015,
58,
3794-3805.
[DOI no: ]
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PubMed id
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Abstract
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Myeloid cell leukemia-1 (Mcl-1) is an antiapoptotic member of the Bcl-2 family
of proteins that is overexpressed and amplified in many cancers. Overexpression
of Mcl-1 allows cancer cells to evade apoptosis and contributes to the
resistance of cancer cells to be effectively treated with various
chemotherapies. From an NMR-based screen of a large fragment library, several
distinct chemical scaffolds that bind to Mcl-1 were discovered. Here, we
describe the discovery of potent tricyclic 2-indole carboxylic acid inhibitors
that exhibit single digit nanomolar binding affinity to Mcl-1 and greater than
1700-fold selectivity over Bcl-xL and greater than 100-fold selectivity over
Bcl-2. X-ray structures of these compounds when complexed to Mcl-1 provide
detailed information on how these small-molecules bind to the target, which was
used to guide compound optimization.
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