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PDBsum entry 5c9c
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Transferase/transferase inhibitor
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PDB id
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5c9c
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References listed in PDB file
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Key reference
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Title
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Inhibition of raf isoforms and active dimers by ly3009120 leads to anti-Tumor activities in ras or braf mutant cancers.
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Authors
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S.B.Peng,
J.R.Henry,
M.D.Kaufman,
W.P.Lu,
B.D.Smith,
S.Vogeti,
T.J.Rutkoski,
S.Wise,
L.Chun,
Y.Zhang,
R.D.Van horn,
T.Yin,
X.Zhang,
V.Yadav,
S.H.Chen,
X.Gong,
X.Ma,
Y.Webster,
S.Buchanan,
I.Mochalkin,
L.Huber,
L.Kays,
G.P.Donoho,
J.Walgren,
D.Mccann,
P.Patel,
I.Conti,
G.D.Plowman,
J.J.Starling,
D.L.Flynn.
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Ref.
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Cancer Cell, 2015,
28,
384-398.
[DOI no: ]
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PubMed id
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Abstract
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LY3009120 is a pan-RAF and RAF dimer inhibitor that inhibits all RAF isoforms
and occupies both protomers in RAF dimers. Biochemical and cellular analyses
revealed that LY3009120 inhibits ARAF, BRAF, and CRAF isoforms with similar
affinity, while vemurafenib or dabrafenib have little or modest CRAF activity
compared to their BRAF activities. LY3009120 induces BRAF-CRAF dimerization but
inhibits the phosphorylation of downstream MEK and ERK, suggesting that it
effectively inhibits the kinase activity of BRAF-CRAF heterodimers. Further
analyses demonstrated that LY3009120 also inhibits various forms of RAF dimers
including BRAF or CRAF homodimers. Due to these unique properties, LY3009120
demonstrates minimal paradoxical activation, inhibits MEK1/2 phosphorylation,
and exhibits anti-tumor activities across multiple models carrying KRAS, NRAS,
or BRAF mutation.
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