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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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PDB id:
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| Name: |
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Apoptosis/apoptosis inhibitor
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Title:
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Mcl-1 complexed with small molecules
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Structure:
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Induced myeloid leukemia cell differentiation protein mcl- 1. Chain: a, b, c, d, e, f, g, h, i, j, k, l. Synonym: bcl-2-like protein 3,bcl2-l-3,bcl-2-related protein eat/mcl1,mcl1/eat. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: mcl1, bcl2l3. Expressed in: escherichia coli. Expression_system_taxid: 562
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Resolution:
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2.50Å
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R-factor:
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0.183
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R-free:
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0.240
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Authors:
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B.Zhao
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Key ref:
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J.P.Burke
et al.
(2015).
Discovery of tricyclic indoles that potently inhibit Mcl-1 using fragment-based methods and structure-based design.
J Med Chem,
58,
3794-3805.
PubMed id:
DOI:
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Date:
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14-Apr-15
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Release date:
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29-Apr-15
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PROCHECK
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Headers
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References
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Q07820
(MCL1_HUMAN) -
Induced myeloid leukemia cell differentiation protein Mcl-1 from Homo sapiens
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Seq:
Struc:
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350 a.a.
152 a.a.*
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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*
PDB and UniProt seqs differ
at 1 residue position (black
cross)
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DOI no:
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J Med Chem
58:3794-3805
(2015)
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PubMed id:
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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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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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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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Links
