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PDBsum entry 3zc5
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References listed in PDB file
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Key reference
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Title
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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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Authors
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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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Ref.
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J Med Chem, 2013,
56,
6651-6665.
[DOI no: ]
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PubMed id
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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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