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PDBsum entry 3og7
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Transferase/transferase inhibitor
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PDB id
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3og7
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References listed in PDB file
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Key reference
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Title
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Clinical efficacy of a raf inhibitor needs broad target blockade in braf-Mutant melanoma.
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Authors
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G.Bollag,
P.Hirth,
J.Tsai,
J.Zhang,
P.N.Ibrahim,
H.Cho,
W.Spevak,
C.Zhang,
Y.Zhang,
G.Habets,
E.A.Burton,
B.Wong,
G.Tsang,
B.L.West,
B.Powell,
R.Shellooe,
A.Marimuthu,
H.Nguyen,
K.Y.Zhang,
D.R.Artis,
J.Schlessinger,
F.Su,
B.Higgins,
R.Iyer,
K.D'Andrea,
A.Koehler,
M.Stumm,
P.S.Lin,
R.J.Lee,
J.Grippo,
I.Puzanov,
K.B.Kim,
A.Ribas,
G.A.Mcarthur,
J.A.Sosman,
P.B.Chapman,
K.T.Flaherty,
X.Xu,
K.L.Nathanson,
K.Nolop.
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Ref.
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Nature, 2010,
467,
596-599.
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PubMed id
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Abstract
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B-RAF is the most frequently mutated protein kinase in human cancers. The
finding that oncogenic mutations in BRAF are common in melanoma, followed by the
demonstration that these tumours are dependent on the RAF/MEK/ERK pathway,
offered hope that inhibition of B-RAF kinase activity could benefit melanoma
patients. Herein, we describe the structure-guided discovery of PLX4032
(RG7204), a potent inhibitor of oncogenic B-RAF kinase activity. Preclinical
experiments demonstrated that PLX4032 selectively blocked the RAF/MEK/ERK
pathway in BRAF mutant cells and caused regression of BRAF mutant xenografts.
Toxicology studies confirmed a wide safety margin consistent with the high
degree of selectivity, enabling Phase 1 clinical trials using a crystalline
formulation of PLX4032 (ref. 5). In a subset of melanoma patients, pathway
inhibition was monitored in paired biopsy specimens collected before treatment
initiation and following two weeks of treatment. This analysis revealed
substantial inhibition of ERK phosphorylation, yet clinical evaluation did not
show tumour regressions. At higher drug exposures afforded by a new amorphous
drug formulation, greater than 80% inhibition of ERK phosphorylation in the
tumours of patients correlated with clinical response. Indeed, the Phase 1
clinical data revealed a remarkably high 81% response rate in metastatic
melanoma patients treated at an oral dose of 960 mg twice daily. These data
demonstrate that BRAF-mutant melanomas are highly dependent on B-RAF kinase
activity.
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