title: The selective intravenous inhibitor of the MET tyrosine kinase SAR125844 inhibits tumor growth in MET-amplified cancer.
abstract: Activation of the MET/HGF pathway is common in human cancer and is thought to promote tumor initiation, metastasis, angiogenesis, and resistance to diverse therapies. We report here the pharmacologic characterization of the triazolopyridazine derivative SAR125844, a potent and highly selective inhibitor of the MET receptor tyrosine kinase (RTK), for intravenous administration. SAR125844 displayed nanomolar activity against the wild-type kinase (IC50 value of 4.2 nmol/L) and the M1250T and Y1235D mutants. Broad biochemical profiling revealed that SAR125844 was highly selective for MET kinase. SAR125844 inhibits MET autophosphorylation in cell-based assays in the nanomolar range, and promotes low nanomolar proapoptotic and antiproliferative activities selectively in cell lines with MET gene amplification or pathway addiction. In two MET-amplified human gastric tumor xenograft models, SNU-5 and Hs 746T, intravenous treatment with SAR125844 leads to potent, dose- and time-dependent inhibition of the MET kinase and to significant impact on downstream PI3K/AKT and RAS/MAPK pathways. Long duration of MET kinase inhibition up to 7 days was achieved with a nanosuspension formulation of SAR125844. Daily or every-2-days intravenous treatment of SAR125844 promoted a dose-dependent tumor regression in MET-amplified human gastric cancer models at tolerated doses without treatment-related body weight loss. Our data demonstrated that SAR125844 is a potent and selective MET kinase inhibitor with a favorable preclinical toxicity profile, supporting its clinical development in patients with MET-amplified and MET pathway-addicted tumors.
authors.affiliation: Sanofi Oncology, Sanofi Research and Development, Vitry-sur-Seine, France.
authors.forename: Coumaran
authors.initials: C
authors.lastname: Egile
authors.affiliation: Sanofi Oncology, Sanofi Research and Development, Vitry-sur-Seine, France.
authors.forename: Mireille
authors.initials: M
authors.lastname: Kenigsberg
authors.affiliation: Sanofi Oncology, Sanofi Research and Development, Vitry-sur-Seine, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Delaisi
authors.affiliation: Sanofi Oncology, Sanofi Research and Development, Vitry-sur-Seine, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Bégassat
authors.affiliation: Sanofi Oncology, Sanofi Research and Development, Vitry-sur-Seine, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Do-Vale
authors.affiliation: Sanofi Oncology, Sanofi Research and Development, Vitry-sur-Seine, France.
authors.forename: Jessica
authors.initials: J
authors.lastname: Mestadier
authors.affiliation: Disposition, Safety and Animal Research, Sanofi Research and Development, Vitry-sur-Seine, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Bonche
authors.affiliation: Lead Generation to Candidate Realization, Sanofi Research and Development, Vitry-sur-Seine, France.
authors.forename: Tsiala
authors.initials: T
authors.lastname: Bénard
authors.affiliation: Sanofi Oncology, Sanofi Research and Development, Vitry-sur-Seine, France.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Nicolas
authors.affiliation: Sanofi Oncology, Sanofi Research and Development, Vitry-sur-Seine, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Valence
authors.affiliation: Sanofi Oncology, Sanofi Research and Development, Vitry-sur-Seine, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Lefranc
authors.affiliation: Sanofi Oncology, Sanofi Research and Development, Vitry-sur-Seine, France.
authors.forename: Elisa
authors.initials: E
authors.lastname: Francesconi
authors.affiliation: Sanofi Oncology, Sanofi Research and Development, Vitry-sur-Seine, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Castell
authors.affiliation: Biotherapeutics, Sanofi Research and Development, Vitry-sur-Seine, France.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Lefebvre
authors.affiliation: Sanofi Oncology, Sanofi Research and Development, Vitry-sur-Seine, France.
authors.forename: Conception
authors.initials: C
authors.lastname: Nemecek
authors.affiliation: Sanofi Oncology, Sanofi Research and Development, Vitry-sur-Seine, France.
authors.forename: Loreley
authors.initials: L
authors.lastname: Calvet
authors.affiliation: Sanofi Oncology, Sanofi Research and Development, Vitry-sur-Seine, France. helene.goulaouic@sanofi.com.
authors.forename: Hélène
authors.initials: H
authors.lastname: Goulaouic
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D061605:Administration, Intravenous; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001393:Azoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D052160:Benzothiazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D005784:Gene Amplification / Q000187:drug effects*; D057809:HEK293 Cells; D006801:Humans; D016513:Mice, SCID; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D013274:Stomach Neoplasms / Q000201:enzymology* / Q000473:pathology*; D014508:Urea / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D001393:Azoles; D052160:Benzothiazoles; D047428:Protein Kinase Inhibitors; C000602444:SAR125844; D000255:Adenosine Triphosphate; D014508:Urea; D019859:Proto-Oncogene Proteins c-met