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PDBsum entry 4r1v
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Transferase/transferase inhibitor
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PDB id
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4r1v
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References listed in PDB file
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Key reference
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Title
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Identification and optimization of pyridazinones as potent and selective c-Met kinase inhibitors.
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Authors
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D.Dorsch,
O.Schadt,
F.Stieber,
M.Meyring,
U.Grädler,
F.Bladt,
M.Friese-Hamim,
C.Knühl,
U.Pehl,
A.Blaukat.
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Ref.
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Bioorg Med Chem Lett, 2015,
25,
1597-1602.
[DOI no: ]
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PubMed id
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Abstract
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In a high-throughput screening campaign for c-Met kinase inhibitors, a
thiadiazinone derivative with a carbamate group was identified as a potent in
vitro inhibitor. Subsequent optimization guided by c-Met-inhibitor X-ray
structures furnished new compound classes with excellent in vitro and in vivo
profiles. The thiadiazinone ring of the HTS hit was first replaced by a
pyridazinone followed by an exchange of the carbamate hinge binder with a
1,5-disubstituted pyrimidine. Finally an optimized compound, 22 (MSC2156119),
with excellent in vitro potency, high kinase selectivity, long half-life after
oral administration and in vivo anti-tumor efficacy at low doses, was selected
as a candidate for clinical development.
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