title: Design, synthesis, and evaluation of novel imidazo[1,2-a][1,3,5]triazines and their derivatives as focal adhesion kinase inhibitors with antitumor activity.
abstract: A series of triazinic inhibitors of focal adhesion kinase (FAK) have been recently shown to exert antiangiogenic activity against HUVEC cells and anticancer efficacy against several cancer cell lines. We report herein that we further explored the heterocyclic core of these inhibitors by a fused imidazole ring with the triazine to provide imidazo[1,2-a][1,3,5]triazines. Importantly, these new compounds displayed 10(-7)-10(-8) M IC50 values, and the best inhibitor showed IC50 value of 50 nM against FAK enzymatic activity. Several inhibitors potently inhibited the proliferation of a panel of cancer cell lines expressing high levels of FAK. Apoptosis analysis in U87-MG and HCT-116 cell lines suggested that these compounds delayed cell cycle progression by arresting cells in the G2/M phase of the cell cycle, retarding cell growth. Further investigation demonstrated that these compounds strongly inhibited cell-matrix adhesion, migration, and invasion of U87-MG cells.
authors.affiliation: Chemistry & Biology, Nucleo(s)tides & Immunology for Therapy (CBNIT), CNRS UMR8601, Université Paris Descartes, PRES Sorbonne Paris Cité, UFR Biomédicale , 45 rue des Saints-Pères, 75270 Cedex 06 Paris, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Dao
authors.forename: Nikaia
authors.initials: N
authors.lastname: Smith
authors.forename: Céline
authors.initials: C
authors.lastname: Tomkiewicz-Raulet
authors.forename: Expédite
authors.initials: E
authors.lastname: Yen-Pon
authors.forename: Marta
authors.initials: M
authors.lastname: Camacho-Artacho
authors.forename: Daniel
authors.initials: D
authors.lastname: Lietha
authors.forename: Jean-Phillipe
authors.initials: JP
authors.lastname: Herbeuval
authors.forename: Xavier
authors.initials: X
authors.lastname: Coumoul
authors.forename: Christiane
authors.initials: C
authors.lastname: Garbay
authors.forename: Huixiong
authors.initials: H
authors.lastname: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D014227:Triazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D014227:Triazines; C000597758:methyl 2-(4-(3,4,5-trimethoxyphenylamino)imidazo(1,2-a)(1,3,5)triazin-2-ylamino)benzoate; D051416:Focal Adhesion Protein-Tyrosine Kinases