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PDBsum entry 5ho6
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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 and pharmacokinetic and pharmacological properties of the potent and selective met kinase inhibitor 1-{6-[6-(4-Fluorophenyl)-[1,2,4]triazolo[4,3-B]pyridazin-3-Ylsulfanyl]benzothiazol-2-Yl}-3-(2-Morpholin-4-Ylethyl)urea (sar125844).
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Authors
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A.Ugolini,
M.Kenigsberg,
A.Rak,
F.Vallée,
J.Houtmann,
M.Lowinski,
C.Capdevila,
J.Khider,
E.Albert,
N.Martinet,
C.Nemecek,
S.Grapinet,
E.Bacqué,
M.Roesner,
C.Delaisi,
L.Calvet,
F.Bonche,
D.Semiond,
C.Egile,
H.Goulaouic,
L.Schio.
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Ref.
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J Med Chem, 2016,
59,
7066-7074.
[DOI no: ]
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PubMed id
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Abstract
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The HGF/MET pathway is frequently activated in a variety of cancer types.
Several selective small molecule inhibitors of the MET kinase are currently in
clinical evaluation, in particular for NSCLC, liver, and gastric cancer
patients. We report herein the discovery of a series of triazolopyridazines that
are selective inhibitors of wild-type (WT) MET kinase and several clinically
relevant mutants. We provide insight into their mode of binding and report
unprecedented crystal structures of the Y1230H variant. A multiparametric
chemical optimization approach allowed the identification of compound 12
(SAR125844) as a development candidate. In this chemical series, absence of
CYP3A4 inhibition was obtained at the expense of satisfactory oral absorption.
Compound 12, a promising parenteral agent for the treatment of MET-dependent
cancers, promoted sustained target engagement at tolerated doses in a human
xenograft tumor model. Preclinical pharmacokinetics conducted in several species
were predictive for the observed pharmacokinetic behavior of 12 in cancer
patients.
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