title: 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).
abstract: 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.
authors.forename: Antonio
authors.initials: A
authors.lastname: Ugolini
authors.forename: Mireille
authors.initials: M
authors.lastname: Kenigsberg
authors.forename: Alexey
authors.initials: A
authors.lastname: Rak
authors.forename: Francois
authors.initials: F
authors.lastname: Vallée
authors.forename: Jacques
authors.initials: J
authors.lastname: Houtmann
authors.forename: Maryse
authors.initials: M
authors.lastname: Lowinski
authors.forename: Cécile
authors.initials: C
authors.lastname: Capdevila
authors.forename: Jean
authors.initials: J
authors.lastname: Khider
authors.forename: Eva
authors.initials: E
authors.lastname: Albert
authors.forename: Nathalie
authors.initials: N
authors.lastname: Martinet
authors.forename: Conception
authors.initials: C
authors.lastname: Nemecek
authors.forename: Sandrine
authors.initials: S
authors.lastname: Grapinet
authors.forename: Eric
authors.initials: E
authors.lastname: Bacqué
authors.affiliation: Sanofi-Aventis Germany GmbH , Industriepark Hoechst, 65926 Frankfurt am Main, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Roesner
authors.forename: Christine
authors.initials: C
authors.lastname: Delaisi
authors.forename: Loreley
authors.initials: L
authors.lastname: Calvet
authors.forename: Fabrice
authors.initials: F
authors.lastname: Bonche
authors.affiliation: Disposition, Safety and Animal Research, Sanofi , 1 Avenue Pierre Brossolette, 91385 Chilly-Mazarin, France.
authors.forename: Dorothée
authors.initials: D
authors.lastname: Semiond
authors.forename: Coumaran
authors.initials: C
authors.lastname: Egile
authors.forename: Hélène
authors.initials: H
authors.lastname: Goulaouic
authors.forename: Laurent
authors.initials: L
authors.lastname: Schio
mesh_terms: D000818:Animals; D052160:Benzothiazoles / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014508:Urea / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D052160:Benzothiazoles; D047428:Protein Kinase Inhibitors; C000602444:SAR125844; D014508:Urea; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met