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PDBsum entry 3c4f
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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 a selective inhibitor of oncogenic b-Raf kinase with potent antimelanoma activity.
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Authors
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J.Tsai,
J.T.Lee,
W.Wang,
J.Zhang,
H.Cho,
S.Mamo,
R.Bremer,
S.Gillette,
J.Kong,
N.K.Haass,
K.Sproesser,
L.Li,
K.S.Smalley,
D.Fong,
Y.L.Zhu,
A.Marimuthu,
H.Nguyen,
B.Lam,
J.Liu,
I.Cheung,
J.Rice,
Y.Suzuki,
C.Luu,
C.Settachatgul,
R.Shellooe,
J.Cantwell,
S.H.Kim,
J.Schlessinger,
K.Y.Zhang,
B.L.West,
B.Powell,
G.Habets,
C.Zhang,
P.N.Ibrahim,
P.Hirth,
D.R.Artis,
M.Herlyn,
G.Bollag.
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Ref.
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Proc Natl Acad Sci U S A, 2008,
105,
3041-3046.
[DOI no: ]
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PubMed id
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Abstract
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BRAF(V600E) is the most frequent oncogenic protein kinase mutation known.
Furthermore, inhibitors targeting "active" protein kinases have demonstrated
significant utility in the therapeutic repertoire against cancer. Therefore, we
pursued the development of specific kinase inhibitors targeting B-Raf, and the
V600E allele in particular. By using a structure-guided discovery approach, a
potent and selective inhibitor of active B-Raf has been discovered. PLX4720, a
7-azaindole derivative that inhibits B-Raf(V600E) with an IC(50) of 13 nM,
defines a class of kinase inhibitor with marked selectivity in both biochemical
and cellular assays. PLX4720 preferentially inhibits the active B-Raf(V600E)
kinase compared with a broad spectrum of other kinases, and potent cytotoxic
effects are also exclusive to cells bearing the V600E allele. Consistent with
the high degree of selectivity, ERK phosphorylation is potently inhibited by
PLX4720 in B-Raf(V600E)-bearing tumor cell lines but not in cells lacking
oncogenic B-Raf. In melanoma models, PLX4720 induces cell cycle arrest and
apoptosis exclusively in B-Raf(V600E)-positive cells. In B-Raf(V600E)-dependent
tumor xenograft models, orally dosed PLX4720 causes significant tumor growth
delays, including tumor regressions, without evidence of toxicity. The work
described here represents the entire discovery process, from initial
identification through structural and biological studies in animal models to a
promising therapeutic for testing in cancer patients bearing B-Raf(V600E)-driven
tumors.
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Figure 1.
Structures of individual compounds leading to the discovery
of PLX4720 are shown. (A) The chemical structure of
3-aminophenyl-7-azaindole (compound 1) is shown beneath its
costructure with Pim-1 kinase. (B) The chemical structure of
3-(3-methoxybenzyl)-7-azaindole (compound 2) is shown beneath
its costructure with the kinase domain of FGFR1. (C) The
chemical structure of PLX4720 is shown beneath its costructure
with B-Raf kinase.
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Figure 2.
Depiction of the three-dimensional structure of PLX4720 bound
to B-Raf. (A) The structure of B-Raf^V600E bound to PLX4720
(yellow) is overlayed with an ATP model based on structures of
ATP analogs in complex with other tyrosine kinases (orange).
This view indicates that the PLX4720 scaffold overlaps with the
adenine-binding site, but the tail of PLX4720 binds to a
different pocket from the ATP ribose-triphosphate tail. The
positions of the hinge, activation loop (A-loop), and
phosphate-binding loop (P-loop) are also shown. (B) A surface
representation shows PLX4720 binding to the B-Raf-selective
pocket in the active conformation. (C) A surface representation
shows PLX4720 binding to the kinase general pocket in the
inactive conformation. (D) A close-up view shows the overlay
PLX4720 bound to both active (green) and inactive (purple)
conformations of the V600 protein, and PLX3203 (yellow) bound to
V600E protein in the active kinase conformation. (E) A
stereoview shows the specific interactions of PLX4720 to the
active kinase conformation. In this conformation, the
phenylalanine of the DFG loop is pointing in toward the
compound-binding site. (F) A stereoview shows the specific
interactions of PLX4720 to the inactive kinase conformation. In
this conformation, the phenylalanine of the DFG loop is pointing
away from the compound-binding site, and binding of PLX4720 is
disfavored, leading to partial occupancy of this site even at
the 1 mM compound concentration used in cocrystallography.
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