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PDBsum entry 4xyf
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Transferase/transferase inhibitor
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PDB id
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4xyf
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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 potent and selective 8-Fluorotriazolopyridine c-Met inhibitors.
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Authors
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E.A.Peterson,
Y.Teffera,
B.K.Albrecht,
D.Bauer,
S.F.Bellon,
A.Boezio,
C.Boezio,
M.A.Broome,
D.Choquette,
K.W.Copeland,
I.Dussault,
R.Lewis,
M.H.Lin,
J.Lohman,
J.Liu,
M.Potashman,
K.Rex,
R.Shimanovich,
D.A.Whittington,
K.R.Vaida,
J.C.Harmange.
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Ref.
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J Med Chem, 2015,
58,
2417-2430.
[DOI no: ]
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PubMed id
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Abstract
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The overexpression of c-Met and/or hepatocyte growth factor (HGF), the
amplification of the MET gene, and mutations in the c-Met kinase domain can
activate signaling pathways that contribute to cancer progression by enabling
tumor cell proliferation, survival, invasion, and metastasis. Herein, we report
the discovery of 8-fluorotriazolopyridines as inhibitors of c-Met activity.
Optimization of the 8-fluorotriazolopyridine scaffold through the combination of
structure-based drug design, SAR studies, and metabolite identification provided
potent (cellular IC50 < 10 nM), selective inhibitors of c-Met with desirable
pharmacokinetic properties that demonstrate potent inhibition of HGF-mediated
c-Met phosphorylation in a mouse liver pharmacodynamic model.
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