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PDBsum entry 3zc5
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PDB id:
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Transferase
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Title:
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X-ray structure of c-met kinase in complex with inhibitor (s)-6-(1-(6- (1-methyl-1h-pyrazol-4-yl)-(1,2,4)triazolo(4,3-b)pyridazin-3-yl) ethyl) quinoline.
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Structure:
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Hepatocyte growth factor receptor. Chain: a. Fragment: tyrosine kinase domain, unp residues 1051-1348. Synonym: hgf receptor, hgf/sf receptor, proto-oncogenE C-met, scatter factor receptor, sf receptor, tyrosine-protein kinase met. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.
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Resolution:
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2.20Å
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R-factor:
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0.204
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R-free:
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0.256
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Authors:
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M.Mctigue,N.Grodsky,K.Ryan
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Key ref:
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J.J.Cui
et al.
(2013).
Lessons from (S)-6-(1-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline (PF-04254644), an inhibitor of receptor tyrosine kinase c-Met with high protein kinase selectivity but broad phosphodiesterase family inhibition leading to myocardial degeneration in rats.
J Med Chem,
56,
6651-6665.
PubMed id:
DOI:
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Date:
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15-Nov-12
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Release date:
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27-Nov-13
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PROCHECK
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Headers
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References
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P08581
(MET_HUMAN) -
Hepatocyte growth factor receptor from Homo sapiens
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Seq:
Struc:
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1390 a.a.
290 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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Enzyme class:
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E.C.2.7.10.1
- receptor protein-tyrosine kinase.
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Reaction:
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L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H+
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L-tyrosyl-[protein]
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+
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ATP
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=
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O-phospho-L-tyrosyl-[protein]
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+
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ADP
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+
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H(+)
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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J Med Chem
56:6651-6665
(2013)
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PubMed id:
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Lessons from (S)-6-(1-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline (PF-04254644), an inhibitor of receptor tyrosine kinase c-Met with high protein kinase selectivity but broad phosphodiesterase family inhibition leading to myocardial degeneration in rats.
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J.J.Cui,
H.Shen,
M.Tran-Dubé,
M.Nambu,
M.McTigue,
N.Grodsky,
K.Ryan,
S.Yamazaki,
S.Aguirre,
M.Parker,
Q.Li,
H.Zou,
J.Christensen.
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ABSTRACT
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The hepatocyte growth factor (HGF)/c-Met signaling axis is deregulated in many
cancers and plays important roles in tumor invasive growth and metastasis. An
exclusively selective c-Met inhibitor
(S)-6-(1-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline
(8) was discovered from a highly selective high-throughput screening hit via
structure-based drug design and medicinal chemistry lead optimization. Compound
8 had many attractive properties meriting preclinical evaluation. Broad
off-target screens identified 8 as a pan-phosphodiesterase (PDE) family
inhibitor, which was implicated in a sustained increase in heart rate, increased
cardiac output, and decreased contractility indices, as well as myocardial
degeneration in in vivo safety evaluations in rats. Compound 8 was terminated as
a preclinical candidate because of a narrow therapeutic window in cardio-related
safety. The learning from multiparameter lead optimization and strategies to
avoid the toxicity attrition at the late stage of drug discovery are discussed.
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