title: Synthesis of novel 1,2,4-triazine scaffold as FAK inhibitors with antitumor activity.
abstract: A series of 1,3,5-triazinic inhibitors of focal adhesion kinase (FAK) has recently been shown to exert antiangiogenic activity against HUVEC cells and anticancer efficacy against several cancer cell lines. In this report, we designed and synthesized a series of new compounds containing a 1,2,4-triazine core as novel scaffold for FAK inhibitors. These compounds displayed 10-7M IC50values, and the best one showed IC50value of 0.23μM against FAK enzymatic activity. Among them, several inhibitors potently inhibited the proliferation of glioblastoma (U-87MG) and colon (HCT-116) cancer cell lines. Docking of compound 10 into the active site of the FAK kinase was performed to explore its potential binding mode.
authors.affiliation: CNRS UMR8601, Université Paris Descartes, PRES Sorbonne Paris Cité, UFR Biomédicale, 45 rue des Saints-Pères, 75270 Paris Cedex 06, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Dao
authors.affiliation: Cell Signalling and Adhesion Group, Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Calle Melchor Fernández Almagro 3, Madrid 28029, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lietha
authors.affiliation: CNRS UMR8601, Université Paris Descartes, PRES Sorbonne Paris Cité, UFR Biomédicale, 45 rue des Saints-Pères, 75270 Paris Cedex 06, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Etheve-Quelquejeu
authors.affiliation: CNRS UMR8601, Université Paris Descartes, PRES Sorbonne Paris Cité, UFR Biomédicale, 45 rue des Saints-Pères, 75270 Paris Cedex 06, France.
authors.forename: Christiane
authors.initials: C
authors.lastname: Garbay
authors.affiliation: CNRS UMR8601, Université Paris Descartes, PRES Sorbonne Paris Cité, UFR Biomédicale, 45 rue des Saints-Pères, 75270 Paris Cedex 06, France. Electronic address: huixiong.chen@parisdescartes.fr.
authors.forename: Huixiong
authors.initials: H
authors.lastname: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014227:Triazines / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D014227:Triazines; C093444:1,2,4-triazine; D051416:Focal Adhesion Protein-Tyrosine Kinases
keywords: 1,2,4-Triazines; Anti-cancer activity; FAK inhibitors; Molecular docking; Synthesis