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)
2016; American Chemical Society; Volume: 59; Issue: 15 Linguagem: Inglês
10.1021/acs.jmedchem.6b00280
ISSN1520-4804
AutoresAntonio Ugolini, Mireille Kenigsberg, Alexey Rak, François Vallée, Jacques Houtmann, Maryse Lowinski, Cécile Capdevila, Jean Khider, Eva Albert, Nathalie Martinet, Conception Nemecek, Sandrine Grapinet, Eric Bacqué, Manfred Roesner, Christine Delaisi, Loreley Calvet, Fabrice Bonche, Dorothée Sémiond, Coumaran Égile, Hélène Goulaouic, Laurent Schio,
Tópico(s)PI3K/AKT/mTOR signaling in cancer
ResumoThe 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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