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PDBsum entry 2pe0
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References listed in PDB file
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Key reference
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Title
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Indolinone based phosphoinositide-Dependent kinase-1 (pdk1) inhibitors. Part 1: design, Synthesis and biological activity.
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Authors
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I.Islam,
J.Bryant,
Y.L.Chou,
M.J.Kochanny,
W.Lee,
G.B.Phillips,
H.Yu,
M.Adler,
M.Whitlow,
E.Ho,
D.Lentz,
M.A.Polokoff,
B.Subramanyam,
J.M.Wu,
D.Zhu,
R.I.Feldman,
D.O.Arnaiz.
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Ref.
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Bioorg Med Chem Lett, 2007,
17,
3814-3818.
[DOI no: ]
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PubMed id
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Abstract
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HTS screening identified 1 with micromolar inhibitory activity against PDK1.
Optimization of 1 afforded 4i (BX-517) which has single-digit nanomolar activity
against PDK1 and excellent selectivity against PKA.
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Secondary reference #1
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Title
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Indolinone based phhosphoinositide-Dependent kinase-1 (pdk1) inhibitors- Part 2: optimization of bx-517
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Authors
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I.Islam,
G.Brown,
J.Bryant,
P.Hrvatin,
M.J.Kochanny,
G.B.Phillips,
S.Yuan,
M.Adler,
M.Whitlow,
D.Lentz,
M.A.Polokoff,
J.Wu,
J.Shen,
J.Walters,
E.Ho,
B.Subramanyam,
D.Zhu,
R.I.Feldman,
D.O.Arnaiz.
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Ref.
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to be published ...
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Secondary reference #2
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Title
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Novel small molecule inhibitors of 3-Phosphoinositide-Dependent kinase-1.
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Authors
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R.I.Feldman,
J.M.Wu,
M.A.Polokoff,
M.J.Kochanny,
H.Dinter,
D.Zhu,
S.L.Biroc,
B.Alicke,
J.Bryant,
S.Yuan,
B.O.Buckman,
D.Lentz,
M.Ferrer,
M.Whitlow,
M.Adler,
S.Finster,
Z.Chang,
D.O.Arnaiz.
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Ref.
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J Biol Chem, 2005,
280,
19867-19874.
[DOI no: ]
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PubMed id
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Figure 1.
FIG. 1. Compound structures for BX-795, BX-912, and BX-320.
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Figure 3.
FIG. 3. Structure of BX-320 bound to the catalytic domain
of PDK1 (PDB code 1Z5M [PDB]
). We crystallized the PDK1 catalytic domain (residues 51-359)
as described by Biondi et al. (30). BX-320 was introduced into
PDK1 crystals and the structure determined from x-ray
diffraction data to a resolution 2.17 angstroms. As shown,
BX-320 binds in the ATP binding pocket, making two hydrogen
bonds through aminopyrimidine nitrogens to Ala^162 located in
the hinge region.
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The above figures are
reproduced from the cited reference
with permission from the ASBMB
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Secondary reference #3
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Title
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High resolution crystal structure of the human pdk1 catalytic domain defines the regulatory phosphopeptide docking site.
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Authors
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R.M.Biondi,
D.Komander,
C.C.Thomas,
J.M.Lizcano,
M.Deak,
D.R.Alessi,
D.M.Van aalten.
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Ref.
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EMBO J, 2002,
21,
4219-4228.
[DOI no: ]
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PubMed id
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Figure 2.
Figure 2 The PIF-pocket. (A) A surface representation of the
putative PIF-binding pocket is shown and compared with the
pocket interacting with the C-terminal FXXF motif in PKA. For
PDK1, the  G-helix
of a symmetry-related molecule is shown as a purple coil, in PKA
the C-terminus is shown as a purple coil. Aromatic amino acids
buried in the pocket are shown as sticks with green carbons,
further side chains interacting with the pocket are shown with
orange carbons. Helix C
is shown as a green ribbon in both PDK1 and PKA. In PDK1, the
ordered sulfate ion and basic residues interacting with it are
also shown. The asterisk indicates residues from the symmetry
related molecule. (B) A stereo image of the residues lining the
PIF/ phosphate-pockets is shown. The PDK1 backbone is shown as a
grey ribbon. Side chains are shown with carbon atoms coloured
orange. Hydrogen bonds to the sulfate ion are shown as black
dotted lines.
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Figure 5.
Figure 5 Interactions of regulatory phosphates with the C-helix.
(A) The PDK1 backbone is shown as a ribbon, with helix C
in the centre of the view. Key residues are shown as sticks with
carbons coloured orange. The sulfate ion and the phosphate on
the activation loop are also shown. A stick model of ATP is
shown with carbons coloured purple. Hydrogen bonds are shown as
black dotted lines. (B) Alignment of the amino acid sequence
forming part of the phosphate pocket on PDK1 with the equivalent
region of the indicated AGC kinases. The residues corresponding
to Lys76, Arg131, Thr148 and Gln150 of PDK1 are indicated in
bold.
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The above figures are
reproduced from the cited reference
which is an Open Access publication published by Macmillan Publishers Ltd
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