title: Identification of new aminoacid amides containing the imidazo[2,1-b]benzothiazol-2-ylphenyl moiety as inhibitors of tumorigenesis by oncogenic Met signaling.
abstract: The Met receptor tyrosine kinase is a promising target in anticancer therapies for its role during tumor evolution and resistance to treatment. It is characterized by an unusual structural plasticity as its active site accepts different inhibitor binding modes. Such feature can be exploited to identify distinct agents targeting tumor dependence and/or resistance by oncogenic Met. Here we report the identification of bioactive agents, featuring a new 4-(imidazo[2,1-b]benzothiazol-2-yl)phenyl moiety, targeting cancer cells dependent on oncogenic Met. One of these compounds (7c; Triflorcas) impairs survival, anchorage-independent growth, and in vivo tumorigenesis, without showing side effects. Our medicinal chemistry strategy was based on an in-house Met-focused library of aminoacid-amide derivatives enriched through structure-based computer modeling, taking into account the Met multiple-binding-mode feature. Altogether, our findings show how a rational structure-based drug design approach coupled to cell-based drug evaluation strategies can be applied in medicinal chemistry to identify new agents targeting a given oncogenic-dependency setting.
authors.affiliation: Aix-Marseille Univ, IBDML, CNRS UMR 6216, Parc Scientifique de Luminy, Case 907, 13288 Marseille, France.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Furlan
authors.forename: Francesco
authors.initials: F
authors.lastname: Colombo
authors.forename: Andrea
authors.initials: A
authors.lastname: Kover
authors.forename: Nathalie
authors.initials: N
authors.lastname: Issaly
authors.forename: Cristina
authors.initials: C
authors.lastname: Tintori
authors.forename: Lucilla
authors.initials: L
authors.lastname: Angeli
authors.forename: Vincent
authors.initials: V
authors.lastname: Leroux
authors.forename: Sébastien
authors.initials: S
authors.lastname: Letard
authors.forename: Mercedes
authors.initials: M
authors.lastname: Amat
authors.forename: Yasmine
authors.initials: Y
authors.lastname: Asses
authors.forename: Bernard
authors.initials: B
authors.lastname: Maigret
authors.forename: Patrice
authors.initials: P
authors.lastname: Dubreuil
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
authors.forename: Rosanna
authors.initials: R
authors.lastname: Dono
authors.forename: Joan
authors.initials: J
authors.lastname: Bosch
authors.forename: Oreste
authors.initials: O
authors.lastname: Piccolo
authors.forename: Daniele
authors.initials: D
authors.lastname: Passarella
authors.forename: Flavio
authors.initials: F
authors.lastname: Maina
mesh_terms: D000577:Amides / Q000737:chemistry* / Q000494:pharmacology*; D000596:Amino Acids / Q000737:chemistry*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004285:Dogs; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000737:chemistry*; D008958:Models, Molecular; D011487:Protein Conformation; D019859:Proto-Oncogene Proteins c-met / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D014584:User-Computer Interface
chemical_list: D000577:Amides; D000596:Amino Acids; D000970:Antineoplastic Agents; D007093:Imidazoles; C029899:imidazole; D019859:Proto-Oncogene Proteins c-met