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PDBsum entry 3vw8
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Transferase/transferase inhibitor
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PDB id
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3vw8
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References listed in PDB file
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Key reference
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Title
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Structure-Based design, Synthesis, And evaluation of imidazo[1,2-B]pyridazine and imidazo[1,2-A]pyridine derivatives as novel dual c-Met and vegfr2 kinase inhibitors.
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Authors
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S.Matsumoto,
N.Miyamoto,
T.Hirayama,
H.Oki,
K.Okada,
M.Tawada,
H.Iwata,
K.Nakamura,
S.Yamasaki,
H.Miki,
A.Hori,
S.Imamura.
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Ref.
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Bioorg Med Chem Lett, 2013,
21,
7686-7698.
[DOI no: ]
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PubMed id
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Abstract
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To identify compounds with potent antitumor efficacy for various human cancers,
we aimed to synthesize compounds that could inhibit c-mesenchymal epithelial
transition factor (c-Met) and vascular endothelial growth factor receptor 2
(VEGFR2) kinases. We designed para-substituted inhibitors by using co-crystal
structural information from c-Met and VEGFR2 in complex with known inhibitors.
This led to the identification of compounds 3a and 3b, which were capable of
suppressing both c-Met and VEGFR2 kinase activities. Further optimization
resulted in pyrazolone and pyridone derivatives, which could form intramolecular
hydrogen bonds to enforce a rigid conformation, thereby producing potent
inhibition. One compound of particular note was the imidazo[1,2-a]pyridine
derivative (26) bearing a 6-methylpyridone ring, which strongly inhibited both
c-Met and VEGFR2 enzyme activities (IC50=1.9, 2.2nM), as well as proliferation
of c-Met-addicted MKN45 cells and VEGF-stimulated human umbilical vein
endothelial cells (IC50=5.0, 1.8nM). Compound 26 exhibited dose-dependent
antitumor efficacy in vivo in MKN45 (treated/control ratio [T/C]=4%, po, 5mg/kg,
once-daily) and COLO205 (T/C=13%, po, 15mg/kg, once-daily) mouse xenograft
models.
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