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

Pascal Dao; Nikaia Smith; Céline Tomkiewicz-Raulet; Expédite Yen-Pon; Marta Camacho-Artacho; Daniel Lietha; Jean-Phillipe Herbeuval; Xavier Coumoul; Christiane Garbay; Huixiong Chen

doi:10.1021/jm500784e

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

J Med Chem. 2015 Jan 8;58(1):237-51. doi: 10.1021/jm500784e. Epub 2014 Sep 11.

Authors

Pascal Dao¹, Nikaia Smith, Céline Tomkiewicz-Raulet, Expédite Yen-Pon, Marta Camacho-Artacho, Daniel Lietha, Jean-Phillipe Herbeuval, Xavier Coumoul, Christiane Garbay, Huixiong Chen

Affiliation

¹ 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.

PMID: 25180654
DOI: 10.1021/jm500784e

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Cell Adhesion / drug effects
Cell Line, Tumor
Cell Movement / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Design
Focal Adhesion Protein-Tyrosine Kinases / antagonists & inhibitors*
Focal Adhesion Protein-Tyrosine Kinases / chemistry
Focal Adhesion Protein-Tyrosine Kinases / metabolism
G2 Phase Cell Cycle Checkpoints / drug effects
HCT116 Cells
Humans
Imidazoles / chemical synthesis
Imidazoles / chemistry
Imidazoles / pharmacology*
Models, Chemical
Models, Molecular
Molecular Structure
Phosphorylation / drug effects
Protein Binding
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Protein Structure, Tertiary
Triazines / chemical synthesis
Triazines / chemistry
Triazines / pharmacology*

Substances

Antineoplastic Agents
Imidazoles
Protein Kinase Inhibitors
Triazines
methyl 2-(4-(3,4,5-trimethoxyphenylamino)imidazo(1,2-a)(1,3,5)triazin-2-ylamino)benzoate
Focal Adhesion Protein-Tyrosine Kinases