Dao Pascal, Lietha Daniel, Etheve-Quelquejeu Mélanie, Garbay Christiane, Chen Huixiong
CNRS UMR8601, Université Paris Descartes, PRES Sorbonne Paris Cité, UFR Biomédicale, 45 rue des Saints-Pères, 75270 Paris Cedex 06, France.
Cell Signalling and Adhesion Group, Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Calle Melchor Fernández Almagro 3, Madrid 28029, Spain.
Bioorg Med Chem Lett. 2017 Apr 15;27(8):1727-1730. doi: 10.1016/j.bmcl.2017.02.072. Epub 2017 Feb 28.
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 10M IC values, and the best one showed IC value 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.
最近有研究表明，一系列1,3,5 - 三嗪类粘着斑激酶（FAK）抑制剂对人脐静脉内皮细胞（HUVEC）具有抗血管生成活性，并对多种癌细胞系具有抗癌功效。在本报告中，我们设计并合成了一系列以1,2,4 - 三嗪为核心的新化合物，作为FAK抑制剂的新型骨架。这些化合物的半数抑制浓度（IC）值为10微摩尔，其中最佳的一种对FAK酶活性的IC值为0.23微摩尔。其中，几种抑制剂能有效抑制胶质母细胞瘤（U - 87MG）和结肠（HCT - 116）癌细胞系的增殖。将化合物10对接至FAK激酶的活性位点，以探究其潜在结合模式。
